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100%;"><div class="u-taCenter"></div><div class="profile--tab_content_container js-tab-pane tab-pane active" id="all"><div class="profile--tab_heading_container js-section-heading" data-section="Papers" id="Papers"><h3 class="profile--tab_heading_container">Papers by Sergei Sukharev</h3></div><div class="js-work-strip profile--work_container" data-work-id="126127930"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/126127930/Active_Role_of_the_Substrate_during_Catalysis_by_the_Therapeutic_Enzyme_L_Asparaginase_II"><img alt="Research paper thumbnail of Active Role of the Substrate during Catalysis by the Therapeutic Enzyme L-Asparaginase II" class="work-thumbnail" src="https://attachments.academia-assets.com/120053125/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/126127930/Active_Role_of_the_Substrate_during_Catalysis_by_the_Therapeutic_Enzyme_L_Asparaginase_II">Active Role of the Substrate during Catalysis by the Therapeutic Enzyme L-Asparaginase II</a></div><div class="wp-workCard_item"><span>Biophysical Journal</span><span>, 2015</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The formation of linear protein fibrils has been previously shown to be enhanced by volume exclus...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The formation of linear protein fibrils has been previously shown to be enhanced by volume exclusion or crowding in the presence of a high concentration of chemically inert protein or polymer, and by adsorption to membrane surfaces. An equilibrium mesoscopic model for the combined effect of both</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="01ad121a8eb8fe6ddaaf8a6ab38bff89" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":120053125,"asset_id":126127930,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/120053125/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="126127930"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="126127930"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 126127930; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589081"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589081/Turgor_and_the_conformational_pathway_for_MscS_recovery"><img alt="Research paper thumbnail of Turgor and the conformational pathway for MscS recovery" class="work-thumbnail" src="https://attachments.academia-assets.com/117986215/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589081/Turgor_and_the_conformational_pathway_for_MscS_recovery">Turgor and the conformational pathway for MscS recovery</a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, Feb 21, 2024</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The bacterial mechanosensitive channel MscS is an adaptive osmolyte release valve that cycles bet...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The bacterial mechanosensitive channel MscS is an adaptive osmolyte release valve that cycles between closed, open, and inactivated states. Since some of these conformations are stable only in the lipid environment under specific conditions, the structures that are currently available cannot explain the entire functional cycle. Previous patch-clamp characterization has provided insights into the missing functional state by estimating protein expansion areas associated with the closed-to-open and closed-to-inactivated transitions and indicating that the closed state must be the most compact. In this paper, we model the conformational transition of MscS from the splayed conformation with the uncoupled gate to the putative compact closed state. The compaction pathway revealed in preliminary extrapolated motion simulations (ExMoS) involved an upward sliding motion of the internal TM3 barrel inside the outer sheath formed by TM1-TM2 helical pairs. This move leads to several structural changes: (1) the relocation of the characteristic kink at G113 to a new position at G121, (2) the establishment of the hydrophobic TM2-TM3 contact, (3) a new pattern of interactions with membrane lipids, and (4) the formation of stabilizing salt bridges between TM1-TM2 loops and the cytoplasmic cage domain. In the intact bacterial cell, the driving force for this upward motion is likely to be turgor pressure normal to the plane of the membrane acting on the upper hemisphere of the cage domain from the inside. Under continuing lipid synthesis in the inner leaflet of the plasma membrane, turgor pressure is also predicted to maximize the lateral pressure of lipids in the membrane, thus driving MscS compaction. Steered simulations were performed on the splayed state to mimic these effects by applying normal forces to the upper part of the cage domain and by applying lateral compression to the TM1-TM2 pairs, emulating the pressure of lipids. The structure arrived at the predicted compact state of the channel. This state was critically stabilized by displacing non-bilayer lipids from the TM2-TM3 crevices into the bilayer. We propose that the energized metabolic state of the cell generating high turgor and promoting lipid synthesis should strongly favor the compact closed state of MscS. The normal forces pressing the dome of the cage domain against the membrane may provide a common recovery mechanism for the entire family of MscS-like channels found exclusively in organisms with walled cells, which evolved to function under turgor pressure. A conversion of turgor into membrane tension under hypoosmotic cytoplasm swelling and peptidoglycan expansion will drive opposite processes of opening followed by adaptive MscS closure and inactivation.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="3119ee05a7e13b75664e3430a8080da6" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986215,"asset_id":123589081,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986215/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589081"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589081"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589081; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589080"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589080/Polymer_extracted_structure_of_the_mechanosensitive_channel_MscS_reveals_the_role_of_protein_lipid_interactions_in_the_gating_cycle"><img alt="Research paper thumbnail of Polymer-extracted structure of the mechanosensitive channel MscS reveals the role of protein-lipid interactions in the gating cycle" class="work-thumbnail" src="https://attachments.academia-assets.com/117986217/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589080/Polymer_extracted_structure_of_the_mechanosensitive_channel_MscS_reveals_the_role_of_protein_lipid_interactions_in_the_gating_cycle">Polymer-extracted structure of the mechanosensitive channel MscS reveals the role of protein-lipid interactions in the gating cycle</a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, Jan 25, 2024</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Abbreviations: mechanosensitive channel (MSC), mechanosensitive channel of small conductance (Msc...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Abbreviations: mechanosensitive channel (MSC), mechanosensitive channel of small conductance (MscS), transmembrane (TM), electron microscopy (EM), Blue Native (BN)</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="b8349cc016b05153cceaedf83fbfc03b" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986217,"asset_id":123589080,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986217/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589080"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589080"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589080; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589079"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589079/On_the_lipid_dependence_of_bacterial_mechanosensitive_channel_gating_in_situ"><img alt="Research paper thumbnail of On the lipid dependence of bacterial mechanosensitive channel gating in situ" class="work-thumbnail" src="https://attachments.academia-assets.com/117986212/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589079/On_the_lipid_dependence_of_bacterial_mechanosensitive_channel_gating_in_situ">On the lipid dependence of bacterial mechanosensitive channel gating in situ</a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, Jan 25, 2024</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">For bacterial mechanosensitive channels acting as turgor-adjusting osmolyte release valves, membr...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">For bacterial mechanosensitive channels acting as turgor-adjusting osmolyte release valves, membrane tension is the primary stimulus driving opening transitions. Because tension is transmitted through the surrounding lipid bilayer, it is possible that the presence or absence of different lipid species may influence the function of these channels. In this work, we characterize the lipid dependence of chromosome-encoded MscS and MscL in E. coli strains with genetically altered lipid composition. We use two previously generated strains that lack one or two major lipid species (PE, PG, or CL) and engineer a third strain that is highly enriched in CL due to the presence of hyperactive cardiolipin synthase ClsA. We characterize the functional behavior of these channels using patch-clamp and quantify the relative tension midpoints, closing rates, inactivation depth, and the rate of recovery back to the closed state. We also measure the osmotic survival of lipid-deficient strains, which characterizes the functional consequences of lipid-mediated channel function at the cell level. We find that the opening and closing behavior of MscS and MscL tolerate the absence of specific lipid species remarkably well. The lack of cardiolipin (CL), however, reduces the active MscS population relative to MscL and decreases the closing rate, slightly increasing the propensity of MscS toward inactivation and slowing the recovery process. The data points to the robustness of the osmolyte release system and the importance of cardiolipin for the adaptive behavior of MscS.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="e2ec33e1e2d24a4d90d0637cd5a5d8c2" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986212,"asset_id":123589079,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986212/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589079"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589079"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589079; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589077"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589077/MSCS_is_a_Critical_Component_for_Osmotic_Survival_of_Vibrio_Cholerae"><img alt="Research paper thumbnail of MSCS is a Critical Component for Osmotic Survival of Vibrio Cholerae" class="work-thumbnail" src="https://attachments.academia-assets.com/117986236/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589077/MSCS_is_a_Critical_Component_for_Osmotic_Survival_of_Vibrio_Cholerae">MSCS is a Critical Component for Osmotic Survival of Vibrio Cholerae</a></div><div class="wp-workCard_item"><span>Biophysical Journal</span><span>, Feb 1, 2020</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">In our research we employ advanced optical microscopy techniques including confocal and deconvolu...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">In our research we employ advanced optical microscopy techniques including confocal and deconvolution microscopies. As the biological model, we use 3T3 mouse embryological fibroblast cells plated on polyacrylamide substrates of various elasticities.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="191f5833b4f3967f48639c7b529bb1f3" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986236,"asset_id":123589077,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986236/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589077"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589077"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589077; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589077]").text(description); $(".js-view-count[data-work-id=123589077]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589077; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589077']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "191f5833b4f3967f48639c7b529bb1f3" } } $('.js-work-strip[data-work-id=123589077]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589077,"title":"MSCS is a Critical Component for Osmotic Survival of Vibrio Cholerae","internal_url":"https://www.academia.edu/123589077/MSCS_is_a_Critical_Component_for_Osmotic_Survival_of_Vibrio_Cholerae","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986236,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986236/thumbnails/1.jpg","file_name":"j.bpj.2019.11.146920240905-1-4nr3d.pdf","download_url":"https://www.academia.edu/attachments/117986236/download_file","bulk_download_file_name":"MSCS_is_a_Critical_Component_for_Osmotic.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986236/j.bpj.2019.11.146920240905-1-4nr3d-libre.pdf?1725556718=\u0026response-content-disposition=attachment%3B+filename%3DMSCS_is_a_Critical_Component_for_Osmotic.pdf\u0026Expires=1740314350\u0026Signature=fIveViMFnlTSSB52BTKLetHNPxXdcPCwU-7Vva1XL7M~mFZiBEilFhZP24ObogAs2pu1hAoCvGfS-ZmyGNdlm2~bVk5MRuUJhAAfs2Feav7kaXH3kVGae5-ER9m1-6loYQBXbRH2gYkXMU-N0ymSEBCqnP298MLHWSP05MCgvBI8pJPL2Zm-dTWMBYvAbLjbo5mB7R8mBKWI1rGbGZiLFPqo5fpzAr7gGRBLxwuxJrOcrehIy1MoNrQcvIvB3GPryxtH1lO1TUZMVue1NbeYujffA9ISElxFGgYbkRp1dUY4QbR9TzWo2fQODitdpsW8Rn9~LKyQMB84YBnEu4JzIg__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589076"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" rel="nofollow" href="https://www.academia.edu/123589076/The_Glutaminase_Activity_Of_L_Asparaginase_Is_Not_Required_For_Anticancer_Activity_Against_Asns_Negative_Cell_Lines"><img alt="Research paper thumbnail of The Glutaminase Activity Of L-Asparaginase Is Not Required For Anticancer Activity Against Asns-Negative Cell Lines" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" rel="nofollow" href="https://www.academia.edu/123589076/The_Glutaminase_Activity_Of_L_Asparaginase_Is_Not_Required_For_Anticancer_Activity_Against_Asns_Negative_Cell_Lines">The Glutaminase Activity Of L-Asparaginase Is Not Required For Anticancer Activity Against Asns-Negative Cell Lines</a></div><div class="wp-workCard_item"><span>Blood</span><span>, Nov 15, 2013</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">L-Asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia therapy. Its mechanism ...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">L-Asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia therapy. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and glutaminase activities. In the present study, we tested the hypothesis that L-ASP glutaminase activity is required for anticancer activity. We first used molecular dynamics simulations of the clinically used E. coli L-ASP enzyme to guide engineering of mutants that lack glutaminase activity. Dynamic mapping of enzyme-substrate contacts identified the backbone amine of residue Q59 as having frequent contact with glutamine but not asparagine substrate. That difference identified Q59 as a promising mutagenesis target for modifying substrate selectivity. Saturation mutagenesis and screening of the resulting Q59 mutants identified Q59L as retaining asparaginase activity yet exhibiting undetectable glutaminase activity. Using Q59L to test the glutaminase-anticancer hypothesis, we observed no anticancer activity by Q59L against cell lines that do express asparagine synthetase (ASNS), including six leukemia lines—CCRF-CEM, SR, MOLT-4, K562, NALM-6, and REH—and two ovarian cancer lines—OVCAR-8 and SK-OV-3. Wild-type (WT) L-ASP, on the other hand, effected a dose-response in all of those cell lines, suggesting that glutaminase activity is required to kill cancer cells that express ASNS. Unexpectedly, Q59L exhibited potent anticancer activity against cell lines that do not express detectable ASNS, including the leukemia cell lines Sup-B15 and RS4;11 and ASNS siRNA-treated OVCAR-8 cells. We conclude that the glutaminase activity of L-ASP is not necessary for anticancer activity against cell types that do not express ASNS. Since Q59L is expected to exhibit reduced toxicity relative to wild-type L-ASP because of its reduced glutaminase activity, these findings provide rationale for clinical assessment of Q59L L-ASP for the treatment of ASNS-deficient cancers. Disclosures: Lorenzi: ERYtech Pharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees, US 7985548, US 7985548 Patents &amp;amp; Royalties. Off Label Use: L-asparaginase is an enzyme-drug approved for treatment of acute lymphoblastic leukemia.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589076"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589076"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589076; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589076]").text(description); $(".js-view-count[data-work-id=123589076]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589076; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589076']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=123589076]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589076,"title":"The Glutaminase Activity Of L-Asparaginase Is Not Required For Anticancer Activity Against Asns-Negative Cell Lines","internal_url":"https://www.academia.edu/123589076/The_Glutaminase_Activity_Of_L_Asparaginase_Is_Not_Required_For_Anticancer_Activity_Against_Asns_Negative_Cell_Lines","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589075"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" rel="nofollow" href="https://www.academia.edu/123589075/MscL_a_Bacterial_Mechanosensitive_Channel"><img alt="Research paper thumbnail of MscL, a Bacterial Mechanosensitive Channel" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" rel="nofollow" href="https://www.academia.edu/123589075/MscL_a_Bacterial_Mechanosensitive_Channel">MscL, a Bacterial Mechanosensitive Channel</a></div><div class="wp-workCard_item"><span>ASM Press eBooks</span><span>, Apr 9, 2014</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">This chapter discusses properties, structure, and the mechanism of gating of the large mechanosen...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">This chapter discusses properties, structure, and the mechanism of gating of the large mechanosensitive (MS) channel MscL, which is probably the best understood tension-gated channel to date. The progress has been rapid, and within 10 years of MscL cloning we have a reasonably supported structural model of gating. The membrane topology determined with the PhoA fusion approach indicated that the short N-terminal (S1, ~15 residues) and the larger C-terminal (S3, ~40 residues) segments are cytoplasmic, whereas the loop connecting M1 and M2 segments (S2, ~25 residues) resides on the extracellular side (periplasm). MscL is activated directly by tension in the lipid bilayer in which the protein is embedded. Upon a strong osmotic downshift, hydrostatic pressure building up inside the cell causes a distension of the elastic cell wall and eventually stresses the inner membrane. Analysis of occupancies of substates and rates of subtransitions as functions of tension provided valuable information about the positions of intermediate states and major barriers on the reaction coordinate. MscL remains stable and functional in liposomes made of exogenous lipids. Initial characterization of MscL using scanning cysteine mutagenesis, site-specific spin labeling, and electron paramagnetic resonance (EPR) spectroscopy demonstrated that the transmembrane region of EcoMscL has essentially the same organization as TbMscL, validating the correctness of the homology-based alignment of the EcoMscL model. The hypothetical S1 bundle was proposed to act as the second gate because a poreoccluding element was needed to explain the postulated expanded low-conducting substate.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589075"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589075"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589075; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589075]").text(description); $(".js-view-count[data-work-id=123589075]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589075; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589075']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=123589075]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589075,"title":"MscL, a Bacterial Mechanosensitive Channel","internal_url":"https://www.academia.edu/123589075/MscL_a_Bacterial_Mechanosensitive_Channel","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589073"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589073/The_voltage_dependence_of_MscL_has_dipolar_and_dielectric_contributions_and_is_governed_by_local_intramembrane_electric_field"><img alt="Research paper thumbnail of The voltage-dependence of MscL has dipolar and dielectric contributions and is governed by local intramembrane electric field" class="work-thumbnail" src="https://attachments.academia-assets.com/117986233/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589073/The_voltage_dependence_of_MscL_has_dipolar_and_dielectric_contributions_and_is_governed_by_local_intramembrane_electric_field">The voltage-dependence of MscL has dipolar and dielectric contributions and is governed by local intramembrane electric field</a></div><div class="wp-workCard_item"><span>Scientific Reports</span><span>, Sep 11, 2018</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Channels without canonical voltage sensors can be modulated by voltage acting on other domains. H...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Channels without canonical voltage sensors can be modulated by voltage acting on other domains. Here we show that besides protein dipoles, pore hydration can be affected by electric fields. In patches, both WT MscL and its V23T mutant show a decrease in the tension midpoint with hyperpolarization. The mutant exhibits a stronger parabolic dependence of transition energy on voltage, highly consistent with the favourable dielectric contribution from water filling the expanding pore. Purified V23T MscL in DPhPC droplet interface bilayers shows a similar voltage dependence. When reconstituted in an asymmetric DOPhPC/DPhPC bilayer carrying a permanent bias of ~130 mV due to a dipole potential difference between the interfaces, the channel behaved as if the local intramembrane electric field sets the tension threshold for gating rather than just the externally applied voltage. The data emphasize the roles of polarized water in the pore and interfacial lipid dipoles in channel gating thermodynamics.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="800f25a0fbd50f0516fa312750a00b50" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986233,"asset_id":123589073,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986233/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589073"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589073"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589073; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589072"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589072/Catalytic_Role_of_the_Substrate_Defines_Specificity_of_Therapeutic_l_Asparaginase"><img alt="Research paper thumbnail of Catalytic Role of the Substrate Defines Specificity of Therapeutic l-Asparaginase" class="work-thumbnail" src="https://attachments.academia-assets.com/117986237/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589072/Catalytic_Role_of_the_Substrate_Defines_Specificity_of_Therapeutic_l_Asparaginase">Catalytic Role of the Substrate Defines Specificity of Therapeutic l-Asparaginase</a></div><div class="wp-workCard_item"><span>Journal of Molecular Biology</span><span>, Aug 1, 2015</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Type II bacterial L-asparaginases (L-ASP) have played an important therapeutic role in cancer tre...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Type II bacterial L-asparaginases (L-ASP) have played an important therapeutic role in cancer treatment for over four decades, yet their exact reaction mechanism remains elusive. L-ASP from E. coli deamidates asparagine (Asn) and glutamine, with a ~10 4 higher specificity (k cat /K m ) for asparagine despite only one methylene difference in length. Through a sensitive kinetic approach, we quantify competition among the substrates and interpret its clinical role. To understand specificity, we use molecular simulations characterize enzyme interactions with substrates and a product (aspartate). We present evidence that the aspartate product in the crystal structure of L-ASP exists in an unusual -COOH protonation state. Consequently, the set of enzyme-product interactions found in the crystal structure, which guided prior mechanistic interpretations, differs from those observed in dynamic simulations of the enzyme with the substrates. Finally, we probe the initial nucleophilic attack with ab initio simulations. The unusual protonation state reappears, suggesting that crystal structures (wild-type and a T89V mutant) represent intermediate steps rather than initial binding. Also, a proton transfers spontaneously to Asn, advancing a new hypothesis that the substrate"s -carboxyl serves as a proton acceptor and activates one of the catalytic threonines during L-ASP"s nucleophilic attack on the amide carbon. That hypothesis explains for the first time why proximity of the substrate -COO -group to the carboxamide is absolutely required for catalysis. The substrate"s catalytic role is likely the determining factor in enzyme specificity as it constrains the allowed distance between the backbone carboxyl and the amide carbon of any L-ASP substrate.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="2593faf7091e4002162f9fb9c9daa0e6" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986237,"asset_id":123589072,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986237/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589072"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589072"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589072; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589072]").text(description); $(".js-view-count[data-work-id=123589072]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589072; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589072']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589071"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589071/Tension_activated_channels_in_the_mechanism_of_osmotic_fitness_in_Pseudomonas_aeruginosa"><img alt="Research paper thumbnail of Tension-activated channels in the mechanism of osmotic fitness in Pseudomonas aeruginosa" class="work-thumbnail" src="https://attachments.academia-assets.com/117986229/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589071/Tension_activated_channels_in_the_mechanism_of_osmotic_fitness_in_Pseudomonas_aeruginosa">Tension-activated channels in the mechanism of osmotic fitness in Pseudomonas aeruginosa</a></div><div class="wp-workCard_item"><span>The Journal of General Physiology</span><span>, Apr 19, 2017</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Pseudomonas aeruginosa (PA) is an opportunistic pathogen with an exceptional ability to adapt to ...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Pseudomonas aeruginosa (PA) is an opportunistic pathogen with an exceptional ability to adapt to a range of environments. Part of its adaptive potential is the ability to survive drastic osmolarity changes. Upon a sudden dilution of external medium, such as during exposure to rain, bacteria evade mechanical rupture by engaging tension-activated channels that act as osmolyte release valves. In this study, we compare fast osmotic permeability responses in suspensions of wild-type PA and Escherichia coli (EC) strains in stopped-flow experiments and provide electrophysiological descriptions of osmotic-release channels in PA. Using osmotic dilution experiments, we first show that PA tolerates a broader range of shocks than EC. We record the kinetics of cell equilibration reported by light scattering responses to osmotic up-and down-shocks. PA exhibits a lower water permeability and faster osmolyte release rates during large osmotic dilutions than EC, which correlates with better survival. To directly characterize the PA tension-activated channels, we generate giant spheroplasts from this microorganism and record current responses in excised patches. Unlike EC, which relies primarily on two types of channels, EcMscS and EcMscL, to generate a distinctive two-wave pressure ramp response, PA exhibits a more gradual response that is dominated by MscL-type channels. Genome analysis, cloning, and expression reveal that PA possesses one MscL-type (PaMscL) and two MscS-type (PaMscS-1 and 2) proteins. In EC spheroplasts, both PaM-scS channels exhibit a slightly earlier activation by pressure compared with EcMscS. Unitary currents reveal that PaMscS-2 has a smaller conductance, higher anionic preference, stronger inactivation, and slower recovery compared with PaMscS-1. We conclude that PA relies on MscL as the major valve defining a high rate of osmolyte release sufficient to curb osmotic swelling under extreme shocks, but it still requires MscS-type channels with a strong propensity to inactivation to properly terminate massive permeability response.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="58277cd6f0558758cba6892131fef143" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986229,"asset_id":123589071,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986229/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589071"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589071"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589071; 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dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "58277cd6f0558758cba6892131fef143" } } $('.js-work-strip[data-work-id=123589071]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589071,"title":"Tension-activated channels in the mechanism of osmotic fitness in Pseudomonas aeruginosa","internal_url":"https://www.academia.edu/123589071/Tension_activated_channels_in_the_mechanism_of_osmotic_fitness_in_Pseudomonas_aeruginosa","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986229,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986229/thumbnails/1.jpg","file_name":"jgp_201611699.pdf","download_url":"https://www.academia.edu/attachments/117986229/download_file","bulk_download_file_name":"Tension_activated_channels_in_the_mechan.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986229/jgp_201611699-libre.pdf?1725556727=\u0026response-content-disposition=attachment%3B+filename%3DTension_activated_channels_in_the_mechan.pdf\u0026Expires=1740314350\u0026Signature=TPJH3TN0AZN8OslS2Gk0TUGdcH8vMPwzzGQCWWrLczT8-flPn5D9rBL08lljTYLIQ-2Lcvn4UD~9SvgV0ncIcVKGLurSZOBugLTY644By85aE710BOwfFScbknyowAZfMNQNt4xNK1wjGyQP~~C4Kf8eudrXmGfwcOWk4WcEMcfPqjbf80kn8F3Q7fY3FX38xawoPuunqZmRh0sK41s84KzYfBloYhV059l9MSRMAtwAfPZ1afAfdUMIK4G0If0pTlVHc0ER98wMhbQxq-otP8t6M6w02cwkp-qsl9umleE1-4jy9MeT6atu1381LTWJ2DeH8LzOgQ~h5fAcjciAXg__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589070"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589070/Effects_on_Membrane_Lateral_Pressure_Suggest_Permeation_Mechanisms_for_Bacterial_Quorum_Signaling_Molecules"><img alt="Research paper thumbnail of Effects on Membrane Lateral Pressure Suggest Permeation Mechanisms for Bacterial Quorum Signaling Molecules" class="work-thumbnail" src="https://attachments.academia-assets.com/117986235/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589070/Effects_on_Membrane_Lateral_Pressure_Suggest_Permeation_Mechanisms_for_Bacterial_Quorum_Signaling_Molecules">Effects on Membrane Lateral Pressure Suggest Permeation Mechanisms for Bacterial Quorum Signaling Molecules</a></div><div class="wp-workCard_item"><span>Biochemistry</span><span>, Jul 21, 2011</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="94c1670f744b9bf7003d5980be24f6fc" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986235,"asset_id":123589070,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986235/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589070"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589070"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589070; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589069"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589069/The_glutaminase_activity_of_l_asparaginase_is_not_required_for_anticancer_activity_against_ASNS_negative_cells"><img alt="Research paper thumbnail of The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells" class="work-thumbnail" src="https://attachments.academia-assets.com/117986228/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589069/The_glutaminase_activity_of_l_asparaginase_is_not_required_for_anticancer_activity_against_ASNS_negative_cells">The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells</a></div><div class="wp-workCard_item"><span>Blood</span><span>, Jun 5, 2014</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">• We used molecular dynamics, saturation mutagenesis, and enzymologic screening to develop a glut...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">• We used molecular dynamics, saturation mutagenesis, and enzymologic screening to develop a glutaminase-free mutant (Q59L) L-ASP. • We then used Q59L to show that glutaminase activity is not required for L-ASP activity against ASNS-negative cancer cells. L-Asparaginase (L-ASP) is a key component of therapy for acute lymphoblastic leukemia. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and glutaminase activities. Here, we show that L-ASP's glutaminase activity is not always required for the enzyme's anticancer effect. We first used molecular dynamics simulations of the clinically standard Escherichia coli L-ASP to predict what mutated forms could be engineered to retain activity against asparagine but not glutamine. Dynamic mapping of enzyme substrate contacts identified Q59 as a promising mutagenesis target for that purpose. Saturation mutagenesis followed by enzymatic screening identified Q59L as a variant that retains asparaginase activity but shows undetectable glutaminase activity. Unlike wild-type L-ASP, Q59L is inactive against cancer cells that express measurable asparagine synthetase (ASNS). Q59L is potently active, however, against ASNS-negative cells. Those observations indicate that the glutaminase activity of L-ASP is necessary for anticancer activity against ASNS-positive cell types but not ASNS-negative cell types. Because the clinical toxicity of L-ASP is thought to stem from its glutaminase activity, these findings suggest the hypothesis that glutaminase-negative variants of L-ASP would provide larger therapeutic indices than wild-type</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5366cafa92bebafa0b17249efe205ba7" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986228,"asset_id":123589069,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986228/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589069"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589069"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589069; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589069]").text(description); $(".js-view-count[data-work-id=123589069]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589069; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589069']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589068"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589068/MscS_inactivation_and_recovery_are_slow_voltage_dependent_processes_sensitive_to_interactions_with_lipids"><img alt="Research paper thumbnail of MscS inactivation and recovery are slow voltage-dependent processes sensitive to interactions with lipids" class="work-thumbnail" src="https://attachments.academia-assets.com/117986210/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589068/MscS_inactivation_and_recovery_are_slow_voltage_dependent_processes_sensitive_to_interactions_with_lipids">MscS inactivation and recovery are slow voltage-dependent processes sensitive to interactions with lipids</a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, May 9, 2023</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Mechanosensitive channel MscS, the major bacterial osmolyte release valve, shows a characteristic...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Mechanosensitive channel MscS, the major bacterial osmolyte release valve, shows a characteristic adaptive behavior. With a sharp onset of activating tension, the channel population readily opens, but under prolonged action of moderate near-threshold tension, it inactivates. The inactivated state is non-conductive and tension-insensitive, which suggests that the gate gets uncoupled from the lipid-facing domains. The kinetic rates for tension-driven opening-closing transitions are 4-6 orders of magnitude higher than the rates for inactivation and recovery. Here we show that inactivation is augmented and recovery is slowed down by depolarization. Hyperpolarization, conversely, impedes inactivation and speeds up recovery. We then address the question of whether protein-lipid interactions may set the rates and influence voltage dependence of inactivation and recovery. Mutations of conserved arginines 46 and 74 anchoring the lipid-facing helices to the inner membrane leaflet to tryptophans do not change the closing transitions, but instead change the kinetics of both inactivation and recovery and essentially eliminate their voltage-dependence. Uncharged polar substitutions (S or Q) for these anchors produce functional channels but increase the inactivation and reduce the recovery rates. The data suggest that it is not the activation and closing transitions, but rather the inactivation and recovery pathways that involve substantial rearrangements of the protein-lipid boundary associated with the separation of the lipid-facing helices from the gate. The discovery that hyperpolarization robustly assists MscS recovery indicates that membrane potential can regulate osmolyte release valves by putting them either on the 'ready' or 'standby' mode depending on the cell's metabolic state.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="3b0b1c1573f4ba4bf72e095379df775c" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986210,"asset_id":123589068,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986210/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589068"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589068"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589068; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589068]").text(description); $(".js-view-count[data-work-id=123589068]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589068; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589068']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "3b0b1c1573f4ba4bf72e095379df775c" } } $('.js-work-strip[data-work-id=123589068]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589068,"title":"MscS inactivation and recovery are slow voltage-dependent processes sensitive to interactions with lipids","internal_url":"https://www.academia.edu/123589068/MscS_inactivation_and_recovery_are_slow_voltage_dependent_processes_sensitive_to_interactions_with_lipids","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986210,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986210/thumbnails/1.jpg","file_name":"2023.05.08.539870.full.pdf","download_url":"https://www.academia.edu/attachments/117986210/download_file","bulk_download_file_name":"MscS_inactivation_and_recovery_are_slow.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986210/2023.05.08.539870.full-libre.pdf?1725556735=\u0026response-content-disposition=attachment%3B+filename%3DMscS_inactivation_and_recovery_are_slow.pdf\u0026Expires=1740314350\u0026Signature=SLs2vQ-JiX-T4AYcBossm2TwJB7vzQi0h1CnqY6QFlcu5IuHa05k7fmpOxsXvhM5-v~~D~C8Qope5Xx62FAqLtVLhMNGyPLO5k~DUTXohx6696D40DaXZIToVAJ-LwJnA4GEQfFNU2LrUjPQigDE11w7g5aAOJBF~Pis3UBU78-h4vMoSCikZBdYFeeyf1gyarYfvIVbwUnNx-0iX4i8SJJsZpGaS1ePA1eM6DcVXRdcjsmN3cQH8nHg6ghSVjyF5mwse4vmndw~ze8MYEbfsy0vhC12PdAXLtdngQ9Z3Dc~Rl6RoHELqSNmiXQzInIVuEqbe1-AitLBD7D10OXxMg__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589067"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589067/MscS_is_a_critical_component_for_osmotic_survival_of_i_Vibrio_cholerae_i_"><img alt="Research paper thumbnail of MscS is a critical component for osmotic survival of<i>Vibrio cholerae</i>" class="work-thumbnail" src="https://attachments.academia-assets.com/117986209/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589067/MscS_is_a_critical_component_for_osmotic_survival_of_i_Vibrio_cholerae_i_">MscS is a critical component for osmotic survival of<i>Vibrio cholerae</i></a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, May 9, 2023</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Intestinal bacteria, including the facultative pathogen Vibrio cholerae, can adapt to a wide rang...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Intestinal bacteria, including the facultative pathogen Vibrio cholerae, can adapt to a wide range of osmotic environments. In high-osmolarity media, bacteria accumulate small compatible metabolites to maintain turgor pressure, but under drastic osmotic down-shifts bacteria are able to avoid mechanical rupture by rapidly releasing these metabolites through mechanosensitive (MS) channels. Previous experiments on V. cholerae have identified two major types of MS channels -MscS and MscL. We functionally examine these channels' specific roles in Vibrio's osmotic rescuing via genetic modification, bacterial patch-clamp electrophysiology, and stopped-flow light scattering. The light scattering kinetics revealed that WT Vibrio cells were capable of releasing up to 10% of their total non-aqueous content within ~30 ms. To investigate each channel's individual contribution to V. cholerae's osmotic permeability response, we generated and characterized the first individual ∆mscS, ∆mscL, and double ∆mscL ∆mscS mutants in V. cholerae O395. Both mutants lacking MscS exhibited delayed osmolyte release kinetics and decreased osmotic survival rates compared to WT. Surprisingly, the ∆mscL mutant had comparable kinetics to WT, but a much higher osmotic survival, whereas ∆mscS had low survival, comparable to the double ∆mscL ∆mscS mutant. The data indicate that MscS is much more efficient in osmotic adjustment and is upregulated in the absence of MscL, whereas in the absence of the low-threshold MscS, MscL even becomes toxic. Kinetic modeling of the cell swelling process and channel activation reveals the advantage of low-threshold MscS in curbing tension surges in Vibrio and its role in proper termination of the osmotic permeability response.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="93d5cdb2d6d92d596dc15d70d79d3045" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986209,"asset_id":123589067,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986209/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589067"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589067"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589067; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589062"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589062/Glutaminase_Activity_of_scp_L_scp_Asparaginase_Contributes_to_Durable_Preclinical_Activity_against_Acute_Lymphoblastic_Leukemia"><img alt="Research paper thumbnail of Glutaminase Activity of <scp>L</scp>-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia" class="work-thumbnail" src="https://attachments.academia-assets.com/117986204/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589062/Glutaminase_Activity_of_scp_L_scp_Asparaginase_Contributes_to_Durable_Preclinical_Activity_against_Acute_Lymphoblastic_Leukemia">Glutaminase Activity of <scp>L</scp>-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia</a></div><div class="wp-workCard_item"><span>Molecular Cancer Therapeutics</span><span>, Sep 1, 2019</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">We and others have reported that the anticancer activity of L-asparaginase (ASNase) against aspar...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">We and others have reported that the anticancer activity of L-asparaginase (ASNase) against asparagine synthetase (ASNS)-positive cell types requires ASNase glutaminase activity, whereas anticancer activity against ASNS-negative cell types does not. Here, we attempted to disentangle the relationship between asparagine metabolism, glutamine metabolism, and downstream pathways that modulate cell viability by testing the hypothesis that ASNase anticancer activity is based on asparagine depletion rather than glutamine deple-tion per se. We tested ASNase wild-type (ASNase WT ) and its glutaminase-deficient Q59L mutant (ASNase Q59L ) and found that ASNase glutaminase activity contributed to durable anticancer activity against xenografts of the ASNS-negative Sup-B15 leukemia cell line in NOD/SCID gamma mice, whereas asparaginase activity alone yielded a mere growth delay. Our findings suggest that ASNase glutaminase activity is necessary for durable, single-agent anticancer activity in vivo, even against ASNS-negative cancer types.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5f1d66ce176884dc6e96f12edb147cb7" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986204,"asset_id":123589062,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986204/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589062"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589062"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589062; 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dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "5f1d66ce176884dc6e96f12edb147cb7" } } $('.js-work-strip[data-work-id=123589062]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589062,"title":"Glutaminase Activity of \u003cscp\u003eL\u003c/scp\u003e-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia","internal_url":"https://www.academia.edu/123589062/Glutaminase_Activity_of_scp_L_scp_Asparaginase_Contributes_to_Durable_Preclinical_Activity_against_Acute_Lymphoblastic_Leukemia","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986204,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986204/thumbnails/1.jpg","file_name":"1587.full.pdf","download_url":"https://www.academia.edu/attachments/117986204/download_file","bulk_download_file_name":"Glutaminase_Activity_of_scp_L_scp_Aspara.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986204/1587.full-libre.pdf?1725556725=\u0026response-content-disposition=attachment%3B+filename%3DGlutaminase_Activity_of_scp_L_scp_Aspara.pdf\u0026Expires=1740314350\u0026Signature=ahhcbMamIknZ94r3GFQ~9uoQIsIKx8u6ol-jFNTaFP798gRTfhYtdad9RyXxFHrONVpD-b7~SSWpHnNCE19L5gZrTpxnR5unD7CNmQEBjOYpIKZP-WIIgQwdH0N~3cdbFUmP4BkfG834TIbEzfR1IltpGAl5RY-gwy2AcC9qYxccwNaqD3LLMBMkSqeHW-aLYw~oSmOQpptlXgCQx~v7XbQkrzCh79YlqQHKvuBAViAj3iRkzNO5Ke~x4c76CEb4UcijF36-sfP3M9EAka~eBqskmjjaSX-K9euRq4liVQ9GsN6YYuNEQW06Zk0Qs7OR2i1jsGoghQWJT0NwDC2b3A__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"},{"id":117986205,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986205/thumbnails/1.jpg","file_name":"1587.full.pdf","download_url":"https://www.academia.edu/attachments/117986205/download_file","bulk_download_file_name":"Glutaminase_Activity_of_scp_L_scp_Aspara.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986205/1587.full-libre.pdf?1725556725=\u0026response-content-disposition=attachment%3B+filename%3DGlutaminase_Activity_of_scp_L_scp_Aspara.pdf\u0026Expires=1740314350\u0026Signature=AiAm7phKELpBWpg25MV6Xv6ofcN1UCW5rT-LlAhL8gOH8AbyrwrQzrfJfEuHKrVJUwgaG8HGynbHyK1rH5J5T36xvfNIvjzegih9IDTdpDVIfXhshrUrSqUC7jRNHNvMZ0m3kVcArzs6At86a4YjefY-58qOR-KtjYruWScTWsUrrMo8GNkHYtGAEDXgZ-At9XsZuYNS4RSiWOwjpVGpUDi~JykaijryIWFlzIufnLOBVBJiICnLSNk01Fi0yyYx76LbjS8f7ChfQwcubZf64vFOQZMe-HstzNWTGUxf9XAaVmC5cSSxepQrXB30aR3OHN56rHeZgU3IxR-NCPgIMA__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589061"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589061/Characterization_of_the_Resting_MscS_Modeling_and_Analysis_of_the_Closed_Bacterial_Mechanosensitive_Channel_of_Small_Conductance"><img alt="Research paper thumbnail of Characterization of the Resting MscS: Modeling and Analysis of the Closed Bacterial Mechanosensitive Channel of Small Conductance" class="work-thumbnail" src="https://attachments.academia-assets.com/117986202/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589061/Characterization_of_the_Resting_MscS_Modeling_and_Analysis_of_the_Closed_Bacterial_Mechanosensitive_Channel_of_Small_Conductance">Characterization of the Resting MscS: Modeling and Analysis of the Closed Bacterial Mechanosensitive Channel of Small Conductance</a></div><div class="wp-workCard_item"><span>Biophysical Journal</span><span>, Feb 1, 2008</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Channels from the MscS family are adaptive tension-activated osmolyte release valves that regulat...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Channels from the MscS family are adaptive tension-activated osmolyte release valves that regulate turgor in prokaryotes and volume in plant chloroplasts. The crystal structure of Escherichia coli MscS has provided a starting point for detailed descriptions of its mechanism. However, solved in the absence of the lipid bilayer, this structure may deviate from a native conformation. In this study, we utilized molecular dynamics simulations and a new iterative extrapolated-motion protocol to pack the splayed peripheral TM1 and TM2 transmembrane helices along the central TM3 shaft. This modification restored the tension transmission route between the membrane and the channel gate. We also modeled the structure of the 26-amino acid N-terminal segments that were unresolved in the crystals. The resulting compact conformation, which we believe approximates the closed resting state of MscS, matches the hydrophobic thickness of the lipid bilayer with arginines 46, 54, and 74 facing the polar lipid headgroups. The pore-lining helices in this resting state feature alternative kinks near the conserved G121 instead of the G113 kinks observed in the crystal structure and the transmembrane barrel remains stable in extended molecular dynamics simulations. Further analysis of the dynamics of the pore constriction revealed several moderately asymmetric and largely dehydrated states. Biochemical and patch-clamp experiments with engineered double-cysteine mutants demonstrated crosslinking between predicted adjacent residue pairs, which formed either spontaneously or under moderate oxidation. The L72C-V99C bridge linking more peripheral TM2 to TM3 caused a shift of channel activation to higher pressures. TM3 to TM3 cross-links through the A84C-T93C, S95C-I97C, and A106C-G108C cysteine pairs were shown to lock MscS in a nonconductive state. Normal channel activity in these mutants could be recovered upon disulfide reduction with dithiothreitol. These results confirmed our modeling predictions of a closed MscS channel featuring a TM3 barrel that largely resembles the crystal conformation though with more tightly packed peripheral helices. From this closed-resting conformation, the TM3 helices must expand to allow for channel opening.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="d9c79352a44e9688ba1e6cb408914c6f" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986202,"asset_id":123589061,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986202/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589061"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589061"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589061; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> </div><div class="profile--tab_content_container js-tab-pane tab-pane" data-section-id="3158800" id="papers"><div class="js-work-strip profile--work_container" data-work-id="126127930"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/126127930/Active_Role_of_the_Substrate_during_Catalysis_by_the_Therapeutic_Enzyme_L_Asparaginase_II"><img alt="Research paper thumbnail of Active Role of the Substrate during Catalysis by the Therapeutic Enzyme L-Asparaginase II" class="work-thumbnail" src="https://attachments.academia-assets.com/120053125/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/126127930/Active_Role_of_the_Substrate_during_Catalysis_by_the_Therapeutic_Enzyme_L_Asparaginase_II">Active Role of the Substrate during Catalysis by the Therapeutic Enzyme L-Asparaginase II</a></div><div class="wp-workCard_item"><span>Biophysical Journal</span><span>, 2015</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The formation of linear protein fibrils has been previously shown to be enhanced by volume exclus...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The formation of linear protein fibrils has been previously shown to be enhanced by volume exclusion or crowding in the presence of a high concentration of chemically inert protein or polymer, and by adsorption to membrane surfaces. An equilibrium mesoscopic model for the combined effect of both</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="01ad121a8eb8fe6ddaaf8a6ab38bff89" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":120053125,"asset_id":126127930,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/120053125/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="126127930"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="126127930"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 126127930; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589081"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589081/Turgor_and_the_conformational_pathway_for_MscS_recovery"><img alt="Research paper thumbnail of Turgor and the conformational pathway for MscS recovery" class="work-thumbnail" src="https://attachments.academia-assets.com/117986215/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589081/Turgor_and_the_conformational_pathway_for_MscS_recovery">Turgor and the conformational pathway for MscS recovery</a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, Feb 21, 2024</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The bacterial mechanosensitive channel MscS is an adaptive osmolyte release valve that cycles bet...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The bacterial mechanosensitive channel MscS is an adaptive osmolyte release valve that cycles between closed, open, and inactivated states. Since some of these conformations are stable only in the lipid environment under specific conditions, the structures that are currently available cannot explain the entire functional cycle. Previous patch-clamp characterization has provided insights into the missing functional state by estimating protein expansion areas associated with the closed-to-open and closed-to-inactivated transitions and indicating that the closed state must be the most compact. In this paper, we model the conformational transition of MscS from the splayed conformation with the uncoupled gate to the putative compact closed state. The compaction pathway revealed in preliminary extrapolated motion simulations (ExMoS) involved an upward sliding motion of the internal TM3 barrel inside the outer sheath formed by TM1-TM2 helical pairs. This move leads to several structural changes: (1) the relocation of the characteristic kink at G113 to a new position at G121, (2) the establishment of the hydrophobic TM2-TM3 contact, (3) a new pattern of interactions with membrane lipids, and (4) the formation of stabilizing salt bridges between TM1-TM2 loops and the cytoplasmic cage domain. In the intact bacterial cell, the driving force for this upward motion is likely to be turgor pressure normal to the plane of the membrane acting on the upper hemisphere of the cage domain from the inside. Under continuing lipid synthesis in the inner leaflet of the plasma membrane, turgor pressure is also predicted to maximize the lateral pressure of lipids in the membrane, thus driving MscS compaction. Steered simulations were performed on the splayed state to mimic these effects by applying normal forces to the upper part of the cage domain and by applying lateral compression to the TM1-TM2 pairs, emulating the pressure of lipids. The structure arrived at the predicted compact state of the channel. This state was critically stabilized by displacing non-bilayer lipids from the TM2-TM3 crevices into the bilayer. We propose that the energized metabolic state of the cell generating high turgor and promoting lipid synthesis should strongly favor the compact closed state of MscS. The normal forces pressing the dome of the cage domain against the membrane may provide a common recovery mechanism for the entire family of MscS-like channels found exclusively in organisms with walled cells, which evolved to function under turgor pressure. A conversion of turgor into membrane tension under hypoosmotic cytoplasm swelling and peptidoglycan expansion will drive opposite processes of opening followed by adaptive MscS closure and inactivation.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="3119ee05a7e13b75664e3430a8080da6" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986215,"asset_id":123589081,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986215/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589081"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589081"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589081; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589080"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589080/Polymer_extracted_structure_of_the_mechanosensitive_channel_MscS_reveals_the_role_of_protein_lipid_interactions_in_the_gating_cycle"><img alt="Research paper thumbnail of Polymer-extracted structure of the mechanosensitive channel MscS reveals the role of protein-lipid interactions in the gating cycle" class="work-thumbnail" src="https://attachments.academia-assets.com/117986217/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589080/Polymer_extracted_structure_of_the_mechanosensitive_channel_MscS_reveals_the_role_of_protein_lipid_interactions_in_the_gating_cycle">Polymer-extracted structure of the mechanosensitive channel MscS reveals the role of protein-lipid interactions in the gating cycle</a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, Jan 25, 2024</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Abbreviations: mechanosensitive channel (MSC), mechanosensitive channel of small conductance (Msc...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Abbreviations: mechanosensitive channel (MSC), mechanosensitive channel of small conductance (MscS), transmembrane (TM), electron microscopy (EM), Blue Native (BN)</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="b8349cc016b05153cceaedf83fbfc03b" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986217,"asset_id":123589080,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986217/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589080"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589080"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589080; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589079"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589079/On_the_lipid_dependence_of_bacterial_mechanosensitive_channel_gating_in_situ"><img alt="Research paper thumbnail of On the lipid dependence of bacterial mechanosensitive channel gating in situ" class="work-thumbnail" src="https://attachments.academia-assets.com/117986212/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589079/On_the_lipid_dependence_of_bacterial_mechanosensitive_channel_gating_in_situ">On the lipid dependence of bacterial mechanosensitive channel gating in situ</a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, Jan 25, 2024</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">For bacterial mechanosensitive channels acting as turgor-adjusting osmolyte release valves, membr...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">For bacterial mechanosensitive channels acting as turgor-adjusting osmolyte release valves, membrane tension is the primary stimulus driving opening transitions. Because tension is transmitted through the surrounding lipid bilayer, it is possible that the presence or absence of different lipid species may influence the function of these channels. In this work, we characterize the lipid dependence of chromosome-encoded MscS and MscL in E. coli strains with genetically altered lipid composition. We use two previously generated strains that lack one or two major lipid species (PE, PG, or CL) and engineer a third strain that is highly enriched in CL due to the presence of hyperactive cardiolipin synthase ClsA. We characterize the functional behavior of these channels using patch-clamp and quantify the relative tension midpoints, closing rates, inactivation depth, and the rate of recovery back to the closed state. We also measure the osmotic survival of lipid-deficient strains, which characterizes the functional consequences of lipid-mediated channel function at the cell level. We find that the opening and closing behavior of MscS and MscL tolerate the absence of specific lipid species remarkably well. The lack of cardiolipin (CL), however, reduces the active MscS population relative to MscL and decreases the closing rate, slightly increasing the propensity of MscS toward inactivation and slowing the recovery process. The data points to the robustness of the osmolyte release system and the importance of cardiolipin for the adaptive behavior of MscS.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="e2ec33e1e2d24a4d90d0637cd5a5d8c2" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986212,"asset_id":123589079,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986212/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589079"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589079"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589079; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589077"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589077/MSCS_is_a_Critical_Component_for_Osmotic_Survival_of_Vibrio_Cholerae"><img alt="Research paper thumbnail of MSCS is a Critical Component for Osmotic Survival of Vibrio Cholerae" class="work-thumbnail" src="https://attachments.academia-assets.com/117986236/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589077/MSCS_is_a_Critical_Component_for_Osmotic_Survival_of_Vibrio_Cholerae">MSCS is a Critical Component for Osmotic Survival of Vibrio Cholerae</a></div><div class="wp-workCard_item"><span>Biophysical Journal</span><span>, Feb 1, 2020</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">In our research we employ advanced optical microscopy techniques including confocal and deconvolu...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">In our research we employ advanced optical microscopy techniques including confocal and deconvolution microscopies. As the biological model, we use 3T3 mouse embryological fibroblast cells plated on polyacrylamide substrates of various elasticities.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="191f5833b4f3967f48639c7b529bb1f3" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986236,"asset_id":123589077,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986236/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589077"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589077"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589077; 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dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "191f5833b4f3967f48639c7b529bb1f3" } } $('.js-work-strip[data-work-id=123589077]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589077,"title":"MSCS is a Critical Component for Osmotic Survival of Vibrio Cholerae","internal_url":"https://www.academia.edu/123589077/MSCS_is_a_Critical_Component_for_Osmotic_Survival_of_Vibrio_Cholerae","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986236,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986236/thumbnails/1.jpg","file_name":"j.bpj.2019.11.146920240905-1-4nr3d.pdf","download_url":"https://www.academia.edu/attachments/117986236/download_file","bulk_download_file_name":"MSCS_is_a_Critical_Component_for_Osmotic.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986236/j.bpj.2019.11.146920240905-1-4nr3d-libre.pdf?1725556718=\u0026response-content-disposition=attachment%3B+filename%3DMSCS_is_a_Critical_Component_for_Osmotic.pdf\u0026Expires=1740314350\u0026Signature=fIveViMFnlTSSB52BTKLetHNPxXdcPCwU-7Vva1XL7M~mFZiBEilFhZP24ObogAs2pu1hAoCvGfS-ZmyGNdlm2~bVk5MRuUJhAAfs2Feav7kaXH3kVGae5-ER9m1-6loYQBXbRH2gYkXMU-N0ymSEBCqnP298MLHWSP05MCgvBI8pJPL2Zm-dTWMBYvAbLjbo5mB7R8mBKWI1rGbGZiLFPqo5fpzAr7gGRBLxwuxJrOcrehIy1MoNrQcvIvB3GPryxtH1lO1TUZMVue1NbeYujffA9ISElxFGgYbkRp1dUY4QbR9TzWo2fQODitdpsW8Rn9~LKyQMB84YBnEu4JzIg__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589076"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" rel="nofollow" href="https://www.academia.edu/123589076/The_Glutaminase_Activity_Of_L_Asparaginase_Is_Not_Required_For_Anticancer_Activity_Against_Asns_Negative_Cell_Lines"><img alt="Research paper thumbnail of The Glutaminase Activity Of L-Asparaginase Is Not Required For Anticancer Activity Against Asns-Negative Cell Lines" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" rel="nofollow" href="https://www.academia.edu/123589076/The_Glutaminase_Activity_Of_L_Asparaginase_Is_Not_Required_For_Anticancer_Activity_Against_Asns_Negative_Cell_Lines">The Glutaminase Activity Of L-Asparaginase Is Not Required For Anticancer Activity Against Asns-Negative Cell Lines</a></div><div class="wp-workCard_item"><span>Blood</span><span>, Nov 15, 2013</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">L-Asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia therapy. Its mechanism ...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">L-Asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia therapy. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and glutaminase activities. In the present study, we tested the hypothesis that L-ASP glutaminase activity is required for anticancer activity. We first used molecular dynamics simulations of the clinically used E. coli L-ASP enzyme to guide engineering of mutants that lack glutaminase activity. Dynamic mapping of enzyme-substrate contacts identified the backbone amine of residue Q59 as having frequent contact with glutamine but not asparagine substrate. That difference identified Q59 as a promising mutagenesis target for modifying substrate selectivity. Saturation mutagenesis and screening of the resulting Q59 mutants identified Q59L as retaining asparaginase activity yet exhibiting undetectable glutaminase activity. Using Q59L to test the glutaminase-anticancer hypothesis, we observed no anticancer activity by Q59L against cell lines that do express asparagine synthetase (ASNS), including six leukemia lines—CCRF-CEM, SR, MOLT-4, K562, NALM-6, and REH—and two ovarian cancer lines—OVCAR-8 and SK-OV-3. Wild-type (WT) L-ASP, on the other hand, effected a dose-response in all of those cell lines, suggesting that glutaminase activity is required to kill cancer cells that express ASNS. Unexpectedly, Q59L exhibited potent anticancer activity against cell lines that do not express detectable ASNS, including the leukemia cell lines Sup-B15 and RS4;11 and ASNS siRNA-treated OVCAR-8 cells. We conclude that the glutaminase activity of L-ASP is not necessary for anticancer activity against cell types that do not express ASNS. Since Q59L is expected to exhibit reduced toxicity relative to wild-type L-ASP because of its reduced glutaminase activity, these findings provide rationale for clinical assessment of Q59L L-ASP for the treatment of ASNS-deficient cancers. Disclosures: Lorenzi: ERYtech Pharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees, US 7985548, US 7985548 Patents &amp;amp; Royalties. Off Label Use: L-asparaginase is an enzyme-drug approved for treatment of acute lymphoblastic leukemia.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589076"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589076"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589076; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589076]").text(description); $(".js-view-count[data-work-id=123589076]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589076; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589076']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=123589076]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589076,"title":"The Glutaminase Activity Of L-Asparaginase Is Not Required For Anticancer Activity Against Asns-Negative Cell Lines","internal_url":"https://www.academia.edu/123589076/The_Glutaminase_Activity_Of_L_Asparaginase_Is_Not_Required_For_Anticancer_Activity_Against_Asns_Negative_Cell_Lines","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589075"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" rel="nofollow" href="https://www.academia.edu/123589075/MscL_a_Bacterial_Mechanosensitive_Channel"><img alt="Research paper thumbnail of MscL, a Bacterial Mechanosensitive Channel" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" rel="nofollow" href="https://www.academia.edu/123589075/MscL_a_Bacterial_Mechanosensitive_Channel">MscL, a Bacterial Mechanosensitive Channel</a></div><div class="wp-workCard_item"><span>ASM Press eBooks</span><span>, Apr 9, 2014</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">This chapter discusses properties, structure, and the mechanism of gating of the large mechanosen...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">This chapter discusses properties, structure, and the mechanism of gating of the large mechanosensitive (MS) channel MscL, which is probably the best understood tension-gated channel to date. The progress has been rapid, and within 10 years of MscL cloning we have a reasonably supported structural model of gating. The membrane topology determined with the PhoA fusion approach indicated that the short N-terminal (S1, ~15 residues) and the larger C-terminal (S3, ~40 residues) segments are cytoplasmic, whereas the loop connecting M1 and M2 segments (S2, ~25 residues) resides on the extracellular side (periplasm). MscL is activated directly by tension in the lipid bilayer in which the protein is embedded. Upon a strong osmotic downshift, hydrostatic pressure building up inside the cell causes a distension of the elastic cell wall and eventually stresses the inner membrane. Analysis of occupancies of substates and rates of subtransitions as functions of tension provided valuable information about the positions of intermediate states and major barriers on the reaction coordinate. MscL remains stable and functional in liposomes made of exogenous lipids. Initial characterization of MscL using scanning cysteine mutagenesis, site-specific spin labeling, and electron paramagnetic resonance (EPR) spectroscopy demonstrated that the transmembrane region of EcoMscL has essentially the same organization as TbMscL, validating the correctness of the homology-based alignment of the EcoMscL model. The hypothetical S1 bundle was proposed to act as the second gate because a poreoccluding element was needed to explain the postulated expanded low-conducting substate.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589075"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589075"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589075; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589075]").text(description); $(".js-view-count[data-work-id=123589075]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589075; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589075']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=123589075]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589075,"title":"MscL, a Bacterial Mechanosensitive Channel","internal_url":"https://www.academia.edu/123589075/MscL_a_Bacterial_Mechanosensitive_Channel","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589073"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589073/The_voltage_dependence_of_MscL_has_dipolar_and_dielectric_contributions_and_is_governed_by_local_intramembrane_electric_field"><img alt="Research paper thumbnail of The voltage-dependence of MscL has dipolar and dielectric contributions and is governed by local intramembrane electric field" class="work-thumbnail" src="https://attachments.academia-assets.com/117986233/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589073/The_voltage_dependence_of_MscL_has_dipolar_and_dielectric_contributions_and_is_governed_by_local_intramembrane_electric_field">The voltage-dependence of MscL has dipolar and dielectric contributions and is governed by local intramembrane electric field</a></div><div class="wp-workCard_item"><span>Scientific Reports</span><span>, Sep 11, 2018</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Channels without canonical voltage sensors can be modulated by voltage acting on other domains. H...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Channels without canonical voltage sensors can be modulated by voltage acting on other domains. Here we show that besides protein dipoles, pore hydration can be affected by electric fields. In patches, both WT MscL and its V23T mutant show a decrease in the tension midpoint with hyperpolarization. The mutant exhibits a stronger parabolic dependence of transition energy on voltage, highly consistent with the favourable dielectric contribution from water filling the expanding pore. Purified V23T MscL in DPhPC droplet interface bilayers shows a similar voltage dependence. When reconstituted in an asymmetric DOPhPC/DPhPC bilayer carrying a permanent bias of ~130 mV due to a dipole potential difference between the interfaces, the channel behaved as if the local intramembrane electric field sets the tension threshold for gating rather than just the externally applied voltage. The data emphasize the roles of polarized water in the pore and interfacial lipid dipoles in channel gating thermodynamics.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="800f25a0fbd50f0516fa312750a00b50" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986233,"asset_id":123589073,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986233/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589073"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589073"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589073; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589072"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589072/Catalytic_Role_of_the_Substrate_Defines_Specificity_of_Therapeutic_l_Asparaginase"><img alt="Research paper thumbnail of Catalytic Role of the Substrate Defines Specificity of Therapeutic l-Asparaginase" class="work-thumbnail" src="https://attachments.academia-assets.com/117986237/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589072/Catalytic_Role_of_the_Substrate_Defines_Specificity_of_Therapeutic_l_Asparaginase">Catalytic Role of the Substrate Defines Specificity of Therapeutic l-Asparaginase</a></div><div class="wp-workCard_item"><span>Journal of Molecular Biology</span><span>, Aug 1, 2015</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Type II bacterial L-asparaginases (L-ASP) have played an important therapeutic role in cancer tre...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Type II bacterial L-asparaginases (L-ASP) have played an important therapeutic role in cancer treatment for over four decades, yet their exact reaction mechanism remains elusive. L-ASP from E. coli deamidates asparagine (Asn) and glutamine, with a ~10 4 higher specificity (k cat /K m ) for asparagine despite only one methylene difference in length. Through a sensitive kinetic approach, we quantify competition among the substrates and interpret its clinical role. To understand specificity, we use molecular simulations characterize enzyme interactions with substrates and a product (aspartate). We present evidence that the aspartate product in the crystal structure of L-ASP exists in an unusual -COOH protonation state. Consequently, the set of enzyme-product interactions found in the crystal structure, which guided prior mechanistic interpretations, differs from those observed in dynamic simulations of the enzyme with the substrates. Finally, we probe the initial nucleophilic attack with ab initio simulations. The unusual protonation state reappears, suggesting that crystal structures (wild-type and a T89V mutant) represent intermediate steps rather than initial binding. Also, a proton transfers spontaneously to Asn, advancing a new hypothesis that the substrate"s -carboxyl serves as a proton acceptor and activates one of the catalytic threonines during L-ASP"s nucleophilic attack on the amide carbon. That hypothesis explains for the first time why proximity of the substrate -COO -group to the carboxamide is absolutely required for catalysis. The substrate"s catalytic role is likely the determining factor in enzyme specificity as it constrains the allowed distance between the backbone carboxyl and the amide carbon of any L-ASP substrate.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="2593faf7091e4002162f9fb9c9daa0e6" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986237,"asset_id":123589072,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986237/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589072"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589072"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589072; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589071"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589071/Tension_activated_channels_in_the_mechanism_of_osmotic_fitness_in_Pseudomonas_aeruginosa"><img alt="Research paper thumbnail of Tension-activated channels in the mechanism of osmotic fitness in Pseudomonas aeruginosa" class="work-thumbnail" src="https://attachments.academia-assets.com/117986229/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589071/Tension_activated_channels_in_the_mechanism_of_osmotic_fitness_in_Pseudomonas_aeruginosa">Tension-activated channels in the mechanism of osmotic fitness in Pseudomonas aeruginosa</a></div><div class="wp-workCard_item"><span>The Journal of General Physiology</span><span>, Apr 19, 2017</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Pseudomonas aeruginosa (PA) is an opportunistic pathogen with an exceptional ability to adapt to ...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Pseudomonas aeruginosa (PA) is an opportunistic pathogen with an exceptional ability to adapt to a range of environments. Part of its adaptive potential is the ability to survive drastic osmolarity changes. Upon a sudden dilution of external medium, such as during exposure to rain, bacteria evade mechanical rupture by engaging tension-activated channels that act as osmolyte release valves. In this study, we compare fast osmotic permeability responses in suspensions of wild-type PA and Escherichia coli (EC) strains in stopped-flow experiments and provide electrophysiological descriptions of osmotic-release channels in PA. Using osmotic dilution experiments, we first show that PA tolerates a broader range of shocks than EC. We record the kinetics of cell equilibration reported by light scattering responses to osmotic up-and down-shocks. PA exhibits a lower water permeability and faster osmolyte release rates during large osmotic dilutions than EC, which correlates with better survival. To directly characterize the PA tension-activated channels, we generate giant spheroplasts from this microorganism and record current responses in excised patches. Unlike EC, which relies primarily on two types of channels, EcMscS and EcMscL, to generate a distinctive two-wave pressure ramp response, PA exhibits a more gradual response that is dominated by MscL-type channels. Genome analysis, cloning, and expression reveal that PA possesses one MscL-type (PaMscL) and two MscS-type (PaMscS-1 and 2) proteins. In EC spheroplasts, both PaM-scS channels exhibit a slightly earlier activation by pressure compared with EcMscS. Unitary currents reveal that PaMscS-2 has a smaller conductance, higher anionic preference, stronger inactivation, and slower recovery compared with PaMscS-1. We conclude that PA relies on MscL as the major valve defining a high rate of osmolyte release sufficient to curb osmotic swelling under extreme shocks, but it still requires MscS-type channels with a strong propensity to inactivation to properly terminate massive permeability response.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="58277cd6f0558758cba6892131fef143" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986229,"asset_id":123589071,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986229/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589071"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589071"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589071; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589070"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589070/Effects_on_Membrane_Lateral_Pressure_Suggest_Permeation_Mechanisms_for_Bacterial_Quorum_Signaling_Molecules"><img alt="Research paper thumbnail of Effects on Membrane Lateral Pressure Suggest Permeation Mechanisms for Bacterial Quorum Signaling Molecules" class="work-thumbnail" src="https://attachments.academia-assets.com/117986235/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589070/Effects_on_Membrane_Lateral_Pressure_Suggest_Permeation_Mechanisms_for_Bacterial_Quorum_Signaling_Molecules">Effects on Membrane Lateral Pressure Suggest Permeation Mechanisms for Bacterial Quorum Signaling Molecules</a></div><div class="wp-workCard_item"><span>Biochemistry</span><span>, Jul 21, 2011</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="94c1670f744b9bf7003d5980be24f6fc" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986235,"asset_id":123589070,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986235/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589070"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589070"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589070; 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dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "94c1670f744b9bf7003d5980be24f6fc" } } $('.js-work-strip[data-work-id=123589070]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589070,"title":"Effects on Membrane Lateral Pressure Suggest Permeation Mechanisms for Bacterial Quorum Signaling Molecules","internal_url":"https://www.academia.edu/123589070/Effects_on_Membrane_Lateral_Pressure_Suggest_Permeation_Mechanisms_for_Bacterial_Quorum_Signaling_Molecules","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986235,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986235/thumbnails/1.jpg","file_name":"19939.pdf","download_url":"https://www.academia.edu/attachments/117986235/download_file","bulk_download_file_name":"Effects_on_Membrane_Lateral_Pressure_Sug.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986235/19939-libre.pdf?1725556720=\u0026response-content-disposition=attachment%3B+filename%3DEffects_on_Membrane_Lateral_Pressure_Sug.pdf\u0026Expires=1740314350\u0026Signature=L3KGJdLghnZZeSE8CyYpVM4PvOVfoO18KmnaSi44b-iZSc47MH56K5nCcq1ur9GXj1ecq~ppc3hpoVklu2M6gdr2s6OX3-31Xrv-2XR6JYM~A341by-5RqadWOry8s7suV4mDbZy46ft2OUL3MhQZC0ffgg7Da-C0LfmwM5gIJEp-Y3NEEWfOigv2fvM4Wza5qau8NWgtU0Oeb-xZq9rBsjNsEzoe8jvpzoPl5EhKi6PAklKU99KpZTxl7s6VTkr4dfKd-UNcQcsQwQ7HEw51pm5qZ6RD0bsh5MaQCv61nEK-7Pi85h3qPTy6VzIrxK4~KeuBieXTjpUtbcwkjZqXw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589069"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589069/The_glutaminase_activity_of_l_asparaginase_is_not_required_for_anticancer_activity_against_ASNS_negative_cells"><img alt="Research paper thumbnail of The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells" class="work-thumbnail" src="https://attachments.academia-assets.com/117986228/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589069/The_glutaminase_activity_of_l_asparaginase_is_not_required_for_anticancer_activity_against_ASNS_negative_cells">The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells</a></div><div class="wp-workCard_item"><span>Blood</span><span>, Jun 5, 2014</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">• We used molecular dynamics, saturation mutagenesis, and enzymologic screening to develop a glut...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">• We used molecular dynamics, saturation mutagenesis, and enzymologic screening to develop a glutaminase-free mutant (Q59L) L-ASP. • We then used Q59L to show that glutaminase activity is not required for L-ASP activity against ASNS-negative cancer cells. L-Asparaginase (L-ASP) is a key component of therapy for acute lymphoblastic leukemia. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and glutaminase activities. Here, we show that L-ASP's glutaminase activity is not always required for the enzyme's anticancer effect. We first used molecular dynamics simulations of the clinically standard Escherichia coli L-ASP to predict what mutated forms could be engineered to retain activity against asparagine but not glutamine. Dynamic mapping of enzyme substrate contacts identified Q59 as a promising mutagenesis target for that purpose. Saturation mutagenesis followed by enzymatic screening identified Q59L as a variant that retains asparaginase activity but shows undetectable glutaminase activity. Unlike wild-type L-ASP, Q59L is inactive against cancer cells that express measurable asparagine synthetase (ASNS). Q59L is potently active, however, against ASNS-negative cells. Those observations indicate that the glutaminase activity of L-ASP is necessary for anticancer activity against ASNS-positive cell types but not ASNS-negative cell types. Because the clinical toxicity of L-ASP is thought to stem from its glutaminase activity, these findings suggest the hypothesis that glutaminase-negative variants of L-ASP would provide larger therapeutic indices than wild-type</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5366cafa92bebafa0b17249efe205ba7" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986228,"asset_id":123589069,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986228/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589069"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589069"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589069; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589068"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589068/MscS_inactivation_and_recovery_are_slow_voltage_dependent_processes_sensitive_to_interactions_with_lipids"><img alt="Research paper thumbnail of MscS inactivation and recovery are slow voltage-dependent processes sensitive to interactions with lipids" class="work-thumbnail" src="https://attachments.academia-assets.com/117986210/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589068/MscS_inactivation_and_recovery_are_slow_voltage_dependent_processes_sensitive_to_interactions_with_lipids">MscS inactivation and recovery are slow voltage-dependent processes sensitive to interactions with lipids</a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, May 9, 2023</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Mechanosensitive channel MscS, the major bacterial osmolyte release valve, shows a characteristic...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Mechanosensitive channel MscS, the major bacterial osmolyte release valve, shows a characteristic adaptive behavior. With a sharp onset of activating tension, the channel population readily opens, but under prolonged action of moderate near-threshold tension, it inactivates. The inactivated state is non-conductive and tension-insensitive, which suggests that the gate gets uncoupled from the lipid-facing domains. The kinetic rates for tension-driven opening-closing transitions are 4-6 orders of magnitude higher than the rates for inactivation and recovery. Here we show that inactivation is augmented and recovery is slowed down by depolarization. Hyperpolarization, conversely, impedes inactivation and speeds up recovery. We then address the question of whether protein-lipid interactions may set the rates and influence voltage dependence of inactivation and recovery. Mutations of conserved arginines 46 and 74 anchoring the lipid-facing helices to the inner membrane leaflet to tryptophans do not change the closing transitions, but instead change the kinetics of both inactivation and recovery and essentially eliminate their voltage-dependence. Uncharged polar substitutions (S or Q) for these anchors produce functional channels but increase the inactivation and reduce the recovery rates. The data suggest that it is not the activation and closing transitions, but rather the inactivation and recovery pathways that involve substantial rearrangements of the protein-lipid boundary associated with the separation of the lipid-facing helices from the gate. The discovery that hyperpolarization robustly assists MscS recovery indicates that membrane potential can regulate osmolyte release valves by putting them either on the 'ready' or 'standby' mode depending on the cell's metabolic state.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="3b0b1c1573f4ba4bf72e095379df775c" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986210,"asset_id":123589068,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986210/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589068"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589068"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589068; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589068]").text(description); $(".js-view-count[data-work-id=123589068]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589068; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589068']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "3b0b1c1573f4ba4bf72e095379df775c" } } $('.js-work-strip[data-work-id=123589068]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589068,"title":"MscS inactivation and recovery are slow voltage-dependent processes sensitive to interactions with lipids","internal_url":"https://www.academia.edu/123589068/MscS_inactivation_and_recovery_are_slow_voltage_dependent_processes_sensitive_to_interactions_with_lipids","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986210,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986210/thumbnails/1.jpg","file_name":"2023.05.08.539870.full.pdf","download_url":"https://www.academia.edu/attachments/117986210/download_file","bulk_download_file_name":"MscS_inactivation_and_recovery_are_slow.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986210/2023.05.08.539870.full-libre.pdf?1725556735=\u0026response-content-disposition=attachment%3B+filename%3DMscS_inactivation_and_recovery_are_slow.pdf\u0026Expires=1740314350\u0026Signature=SLs2vQ-JiX-T4AYcBossm2TwJB7vzQi0h1CnqY6QFlcu5IuHa05k7fmpOxsXvhM5-v~~D~C8Qope5Xx62FAqLtVLhMNGyPLO5k~DUTXohx6696D40DaXZIToVAJ-LwJnA4GEQfFNU2LrUjPQigDE11w7g5aAOJBF~Pis3UBU78-h4vMoSCikZBdYFeeyf1gyarYfvIVbwUnNx-0iX4i8SJJsZpGaS1ePA1eM6DcVXRdcjsmN3cQH8nHg6ghSVjyF5mwse4vmndw~ze8MYEbfsy0vhC12PdAXLtdngQ9Z3Dc~Rl6RoHELqSNmiXQzInIVuEqbe1-AitLBD7D10OXxMg__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589067"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589067/MscS_is_a_critical_component_for_osmotic_survival_of_i_Vibrio_cholerae_i_"><img alt="Research paper thumbnail of MscS is a critical component for osmotic survival of<i>Vibrio cholerae</i>" class="work-thumbnail" src="https://attachments.academia-assets.com/117986209/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589067/MscS_is_a_critical_component_for_osmotic_survival_of_i_Vibrio_cholerae_i_">MscS is a critical component for osmotic survival of<i>Vibrio cholerae</i></a></div><div class="wp-workCard_item"><span>bioRxiv (Cold Spring Harbor Laboratory)</span><span>, May 9, 2023</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Intestinal bacteria, including the facultative pathogen Vibrio cholerae, can adapt to a wide rang...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Intestinal bacteria, including the facultative pathogen Vibrio cholerae, can adapt to a wide range of osmotic environments. In high-osmolarity media, bacteria accumulate small compatible metabolites to maintain turgor pressure, but under drastic osmotic down-shifts bacteria are able to avoid mechanical rupture by rapidly releasing these metabolites through mechanosensitive (MS) channels. Previous experiments on V. cholerae have identified two major types of MS channels -MscS and MscL. We functionally examine these channels' specific roles in Vibrio's osmotic rescuing via genetic modification, bacterial patch-clamp electrophysiology, and stopped-flow light scattering. The light scattering kinetics revealed that WT Vibrio cells were capable of releasing up to 10% of their total non-aqueous content within ~30 ms. To investigate each channel's individual contribution to V. cholerae's osmotic permeability response, we generated and characterized the first individual ∆mscS, ∆mscL, and double ∆mscL ∆mscS mutants in V. cholerae O395. Both mutants lacking MscS exhibited delayed osmolyte release kinetics and decreased osmotic survival rates compared to WT. Surprisingly, the ∆mscL mutant had comparable kinetics to WT, but a much higher osmotic survival, whereas ∆mscS had low survival, comparable to the double ∆mscL ∆mscS mutant. The data indicate that MscS is much more efficient in osmotic adjustment and is upregulated in the absence of MscL, whereas in the absence of the low-threshold MscS, MscL even becomes toxic. Kinetic modeling of the cell swelling process and channel activation reveals the advantage of low-threshold MscS in curbing tension surges in Vibrio and its role in proper termination of the osmotic permeability response.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="93d5cdb2d6d92d596dc15d70d79d3045" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986209,"asset_id":123589067,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986209/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589067"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589067"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589067; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589067]").text(description); $(".js-view-count[data-work-id=123589067]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589067; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589067']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "93d5cdb2d6d92d596dc15d70d79d3045" } } $('.js-work-strip[data-work-id=123589067]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589067,"title":"MscS is a critical component for osmotic survival of\u003ci\u003eVibrio cholerae\u003c/i\u003e","internal_url":"https://www.academia.edu/123589067/MscS_is_a_critical_component_for_osmotic_survival_of_i_Vibrio_cholerae_i_","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986209,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986209/thumbnails/1.jpg","file_name":"2023.05.08.539864.full.pdf","download_url":"https://www.academia.edu/attachments/117986209/download_file","bulk_download_file_name":"MscS_is_a_critical_component_for_osmotic.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986209/2023.05.08.539864.full-libre.pdf?1725556731=\u0026response-content-disposition=attachment%3B+filename%3DMscS_is_a_critical_component_for_osmotic.pdf\u0026Expires=1740314350\u0026Signature=O823T5xkT2HQL2S1oNK-oK5wmAzvGTs9BsB1UnCOpDqgPLXz2ap6o92Yb-rpXLlbxWBt-IjSNTgG3VgW8zud9IaISbt77LeeLKIUjtr6Y5FY94D3fWegmxZY7vcLCPrM72QYL0rwLZvslVorLAdOS7PbOzlQZWO-aK9cLrNuHJ-zRRnTcXzfhbhMEeRDRDzeCbleLVFttIBOKbp1hYsLWOJfFwxespwCptgu2M~dhvkVlwdOKkMA-3gwszMnCR-CMg-NmdNg~GCaEaddVYio67KA5LT-cYcVSGQUuVVhCsUd0G4r09JA-bL4DCS4NqYLb7XZ~JuSKV4INhcbWBng7Q__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589066"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" rel="nofollow" href="https://www.academia.edu/123589066/The_role_of_protein_membrane_electrostatic_interactions_in_the_adaptive_gating_cycle_of_MscS"><img alt="Research paper thumbnail of The role of protein-membrane electrostatic interactions in the adaptive gating cycle of MscS" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" rel="nofollow" href="https://www.academia.edu/123589066/The_role_of_protein_membrane_electrostatic_interactions_in_the_adaptive_gating_cycle_of_MscS">The role of protein-membrane electrostatic interactions in the adaptive gating cycle of MscS</a></div><div class="wp-workCard_item"><span>Biophysical Journal</span><span>, Feb 1, 2023</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589066"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589066"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589066; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589066]").text(description); $(".js-view-count[data-work-id=123589066]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589066; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589066']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); 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window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589065]").text(description); $(".js-view-count[data-work-id=123589065]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589065; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589065']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "31838f65f41408079bfe766de4a081e7" } } $('.js-work-strip[data-work-id=123589065]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589065,"title":"Inactivation of the Bacterial Mechanosensitive Channel MscL Involves Flexible Transmembrane Helices and a ‘Dry’ Gate","internal_url":"https://www.academia.edu/123589065/Inactivation_of_the_Bacterial_Mechanosensitive_Channel_MscL_Involves_Flexible_Transmembrane_Helices_and_a_Dry_Gate","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986231,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986231/thumbnails/1.jpg","file_name":"pdf.pdf","download_url":"https://www.academia.edu/attachments/117986231/download_file","bulk_download_file_name":"Inactivation_of_the_Bacterial_Mechanosen.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986231/pdf-libre.pdf?1725556718=\u0026response-content-disposition=attachment%3B+filename%3DInactivation_of_the_Bacterial_Mechanosen.pdf\u0026Expires=1740314350\u0026Signature=GN6HFRff6ptaeNe7rJ0Ulp0-0H3dahlgA4kBT81Nf4fjPvlOVnYA1FHooCvGpapAdvDICRxzPh2ip6idDTS3Ey1svaWjin2bKP5XnyL2dAO9uuvOIOipAy8NH0ZgPIN5y5SrGmf9IZL8DUQsGiFlC4RCRTV2ZD8sjLScFgaPXcuXeJeh74~muX9Tph5MUvXTsGkJ-lkrZb5cDPil7HDbqM4HbAfK6CYTO5mwjeMjuJHdPB6G7759vQ6ES1l1mwRcHIQr~M0E-Ycg5iBPIxIVw90H0jQzamzAbOOJyrMqWsO6CR23ecv3QKzG-Cd4xT9OBzf~iiTa1sitGHx6fzqQZw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589063"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589063/The_pathway_and_spatial_scale_for_MscS_inactivation"><img alt="Research paper thumbnail of The pathway and spatial scale for MscS inactivation" class="work-thumbnail" src="https://attachments.academia-assets.com/117986207/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589063/The_pathway_and_spatial_scale_for_MscS_inactivation">The pathway and spatial scale for MscS inactivation</a></div><div class="wp-workCard_item"><span>The Journal of General Physiology</span><span>, Jun 13, 2011</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="409494b3c7e981d180f2d3c5eea08e11" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986207,"asset_id":123589063,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986207/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589063"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589063"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589063; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=123589063]").text(description); $(".js-view-count[data-work-id=123589063]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 123589063; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='123589063']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-a9bf3a2bc8c89fa2a77156577594264ee8a0f214d74241bc0fcd3f69f8d107ac.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "409494b3c7e981d180f2d3c5eea08e11" } } $('.js-work-strip[data-work-id=123589063]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":123589063,"title":"The pathway and spatial scale for MscS inactivation","internal_url":"https://www.academia.edu/123589063/The_pathway_and_spatial_scale_for_MscS_inactivation","owner_id":32819717,"coauthors_can_edit":true,"owner":{"id":32819717,"first_name":"Sergei","middle_initials":null,"last_name":"Sukharev","page_name":"SergeiSukharev","domain_name":"umd","created_at":"2015-07-05T18:34:07.150-07:00","display_name":"Sergei Sukharev","url":"https://umd.academia.edu/SergeiSukharev"},"attachments":[{"id":117986207,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986207/thumbnails/1.jpg","file_name":"49.full.pdf","download_url":"https://www.academia.edu/attachments/117986207/download_file","bulk_download_file_name":"The_pathway_and_spatial_scale_for_MscS_i.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986207/49.full-libre.pdf?1725556732=\u0026response-content-disposition=attachment%3B+filename%3DThe_pathway_and_spatial_scale_for_MscS_i.pdf\u0026Expires=1740314350\u0026Signature=SNGT0Ka13X4vZ~8XGHDmaED3fFlDhPIF0ooGi6o0K3zU1cOjkSBruBJ9BU44sN~ULoFEeVYZz0y3TI0zWKGH7SKALL~vlQooyifacqN8oMrQ~mxxrjKOgMKFYIGDzrvobLPni-VFk3wiHPZA4p~b3A6xKaQuucnfFRSb60jk3fjSwQTzkPyafHPKYRjNIH6NqD62P9RIuyMEs~XLItzKsx4roN-si8-6n6UrOd-iXZ0bsM4NlrjS2yUcJZAABk2m6lOqUe6NclzVhRjJj~iGMfGI3j8ti6tjfSnUGEdwPdRhLfNbQgeEPd259svnBw1R7TFX0~pjz3A9R8YnlE74EQ__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"},{"id":117986206,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/117986206/thumbnails/1.jpg","file_name":"49.full.pdf","download_url":"https://www.academia.edu/attachments/117986206/download_file","bulk_download_file_name":"The_pathway_and_spatial_scale_for_MscS_i.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/117986206/49.full-libre.pdf?1725556732=\u0026response-content-disposition=attachment%3B+filename%3DThe_pathway_and_spatial_scale_for_MscS_i.pdf\u0026Expires=1740314350\u0026Signature=a29664hu8w4Pnl4v9kS4FmY8Bj7zVNdoWTVvTTkQnaDGrqotvGcI1b0gEu8uzF-4LK32vo5kQf4fBVSdQZ3GKrFU3V1UFZ4bbYn01-VdRFNvnqxTi9WRZ19~GvUL-rX2RKMWmCxPKa5n4Ei6T39L8QWxLCpP4wVXNsAr5Gzn~TZZhkbrDEc3ExRFUFML9FZl~OqdvRjYgZuUZL6JbQx2DqbhNqmcQJLBaZwF7868gyKfPjuDH69vBpqFE4tWOaR-OBd7QTA4Bdc7kh2f~GaUNJKtyOAn8HT050vyk~j-mZ9IAg94Q5bDzAUSnto~tEOpQ1lnYbYeQ9nqhuFMI7s2IA__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589062"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589062/Glutaminase_Activity_of_scp_L_scp_Asparaginase_Contributes_to_Durable_Preclinical_Activity_against_Acute_Lymphoblastic_Leukemia"><img alt="Research paper thumbnail of Glutaminase Activity of <scp>L</scp>-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia" class="work-thumbnail" src="https://attachments.academia-assets.com/117986204/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589062/Glutaminase_Activity_of_scp_L_scp_Asparaginase_Contributes_to_Durable_Preclinical_Activity_against_Acute_Lymphoblastic_Leukemia">Glutaminase Activity of <scp>L</scp>-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia</a></div><div class="wp-workCard_item"><span>Molecular Cancer Therapeutics</span><span>, Sep 1, 2019</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">We and others have reported that the anticancer activity of L-asparaginase (ASNase) against aspar...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">We and others have reported that the anticancer activity of L-asparaginase (ASNase) against asparagine synthetase (ASNS)-positive cell types requires ASNase glutaminase activity, whereas anticancer activity against ASNS-negative cell types does not. Here, we attempted to disentangle the relationship between asparagine metabolism, glutamine metabolism, and downstream pathways that modulate cell viability by testing the hypothesis that ASNase anticancer activity is based on asparagine depletion rather than glutamine deple-tion per se. We tested ASNase wild-type (ASNase WT ) and its glutaminase-deficient Q59L mutant (ASNase Q59L ) and found that ASNase glutaminase activity contributed to durable anticancer activity against xenografts of the ASNS-negative Sup-B15 leukemia cell line in NOD/SCID gamma mice, whereas asparaginase activity alone yielded a mere growth delay. Our findings suggest that ASNase glutaminase activity is necessary for durable, single-agent anticancer activity in vivo, even against ASNS-negative cancer types.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5f1d66ce176884dc6e96f12edb147cb7" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986204,"asset_id":123589062,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986204/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589062"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589062"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589062; 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="123589061"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/123589061/Characterization_of_the_Resting_MscS_Modeling_and_Analysis_of_the_Closed_Bacterial_Mechanosensitive_Channel_of_Small_Conductance"><img alt="Research paper thumbnail of Characterization of the Resting MscS: Modeling and Analysis of the Closed Bacterial Mechanosensitive Channel of Small Conductance" class="work-thumbnail" src="https://attachments.academia-assets.com/117986202/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/123589061/Characterization_of_the_Resting_MscS_Modeling_and_Analysis_of_the_Closed_Bacterial_Mechanosensitive_Channel_of_Small_Conductance">Characterization of the Resting MscS: Modeling and Analysis of the Closed Bacterial Mechanosensitive Channel of Small Conductance</a></div><div class="wp-workCard_item"><span>Biophysical Journal</span><span>, Feb 1, 2008</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Channels from the MscS family are adaptive tension-activated osmolyte release valves that regulat...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Channels from the MscS family are adaptive tension-activated osmolyte release valves that regulate turgor in prokaryotes and volume in plant chloroplasts. The crystal structure of Escherichia coli MscS has provided a starting point for detailed descriptions of its mechanism. However, solved in the absence of the lipid bilayer, this structure may deviate from a native conformation. In this study, we utilized molecular dynamics simulations and a new iterative extrapolated-motion protocol to pack the splayed peripheral TM1 and TM2 transmembrane helices along the central TM3 shaft. This modification restored the tension transmission route between the membrane and the channel gate. We also modeled the structure of the 26-amino acid N-terminal segments that were unresolved in the crystals. The resulting compact conformation, which we believe approximates the closed resting state of MscS, matches the hydrophobic thickness of the lipid bilayer with arginines 46, 54, and 74 facing the polar lipid headgroups. The pore-lining helices in this resting state feature alternative kinks near the conserved G121 instead of the G113 kinks observed in the crystal structure and the transmembrane barrel remains stable in extended molecular dynamics simulations. Further analysis of the dynamics of the pore constriction revealed several moderately asymmetric and largely dehydrated states. Biochemical and patch-clamp experiments with engineered double-cysteine mutants demonstrated crosslinking between predicted adjacent residue pairs, which formed either spontaneously or under moderate oxidation. The L72C-V99C bridge linking more peripheral TM2 to TM3 caused a shift of channel activation to higher pressures. TM3 to TM3 cross-links through the A84C-T93C, S95C-I97C, and A106C-G108C cysteine pairs were shown to lock MscS in a nonconductive state. Normal channel activity in these mutants could be recovered upon disulfide reduction with dithiothreitol. These results confirmed our modeling predictions of a closed MscS channel featuring a TM3 barrel that largely resembles the crystal conformation though with more tightly packed peripheral helices. From this closed-resting conformation, the TM3 helices must expand to allow for channel opening.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="d9c79352a44e9688ba1e6cb408914c6f" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":117986202,"asset_id":123589061,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/117986202/download_file?s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="123589061"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="123589061"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 123589061; 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