A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis

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Here, we show that unexpectedly the ∼40-residue GPS motif represents …"><meta name="keywords" content="pmid:22333914, PMC3321182, doi:10.1038/emboj.2012.26, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Demet Araç, Antony A Boucard, Axel T Brunger, Amino Acid Sequence, Animals, Cell Adhesion / genetics, Cells, Cultured, Conserved Sequence*, Evolution, Molecular*, HEK293 Cells, Humans, Hydrolysis, Mice, Models, Molecular, Molecular Sequence Data, Mutation / genetics, Nerve Tissue Proteins / genetics, Nerve Tissue Proteins / metabolism, Polycystic Kidney Diseases / genetics, Polycystic Kidney Diseases / metabolism, Protein Folding, Protein Structure, Tertiary, Proteolysis, Rats, Receptors, G-Protein-Coupled / chemistry*, Receptors, G-Protein-Coupled / genetics*, Receptors, G-Protein-Coupled / metabolism, Receptors, Peptide / genetics, Receptors, Peptide / metabolism, TRPP Cation Channels / genetics, TRPP Cation Channels / metabolism, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/22333914/"><meta property="og:description" content="The G protein-coupled receptor (GPCR) Proteolysis Site (GPS) of cell-adhesion GPCRs and polycystic kidney disease (PKD) proteins constitutes a highly conserved autoproteolysis sequence, but its catalytic mechanism remains unknown. Here, we show that unexpectedly the ∼40-residue GPS motif represents …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/22333914/"><meta name="twitter:description" content="The G protein-coupled receptor (GPCR) Proteolysis Site (GPS) of cell-adhesion GPCRs and polycystic kidney disease (PKD) proteins constitutes a highly conserved autoproteolysis sequence, but its catalytic mechanism remains unknown. Here, we show that unexpectedly the ∼40-residue GPS motif represents …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">  <link rel="search" type="application/opensearchdescription+xml" href="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/opensearch.xml" title="PubMed search">  <noscript> <link rel="stylesheet" type="text/css" href="https://cdn.ncbi.nlm.nih.gov/pubmed/277eb475-38df-4990-a0ee-0080b04e86fc/core/no-script.css"> </noscript> <meta name="citation_title" content="A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis"> <meta name="citation_authors" content="Araç D;Boucard AA;Bolliger MF;Nguyen J;Soltis SM;Südhof TC;Brunger AT;"> <meta name="citation_date" content="03/21/2012"> <meta name="citation_publisher" content="EMBO J"> <meta name="citation_journal_title" content="The EMBO journal"> <meta name="citation_pmid" content="22333914"> <meta name="citation_abstract_html_url" content="https://pubmed.ncbi.nlm.nih.gov/22333914/"> <meta name="citation_volume" content="31"> <meta name="citation_issue" content="6"> <meta name="citation_doi" content="10.1038/emboj.2012.26"> <meta name="citation_issn" content="1460-2075"> <link rel="canonical" href="https://pubmed.ncbi.nlm.nih.gov/22333914/" /> </head> <body > <noscript> <div class="no-script-banner" id="no-script-banner"> <div class="warning-message"> <div class="warning-message-text"> This site needs JavaScript to work properly. 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new collection</label> </li> <li> <input type="radio" id="collections-action-panel-existing" class="collections-existing" name="collections" value="existing" checked="true" data-ga-category="save_share" data-ga-action="collections" data-ga-label="collections_radio_existing"> <label for="collections-action-panel-existing">Add to an existing collection</label> </li> </ul> </div> <div class="controls-wrapper"> <div class="action-panel-control-wrap new-collections-controls"> <label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk"> Name your collection: </label> <input type="text" name="add-to-new-collection" id="collections-action-panel-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="save_share" data-ga-action="create_collection" data-ga-label="non_favorties_collection"> <div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="XNW0XMaiuOhIyp0cFGMHwhdrwzdy6NQWS6943t1uztDEoaYiy39IQIwlB9JyzGUW"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="XNW0XMaiuOhIyp0cFGMHwhdrwzdy6NQWS6943t1uztDEoaYiy39IQIwlB9JyzGUW"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="XNW0XMaiuOhIyp0cFGMHwhdrwzdy6NQWS6943t1uztDEoaYiy39IQIwlB9JyzGUW"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="XNW0XMaiuOhIyp0cFGMHwhdrwzdy6NQWS6943t1uztDEoaYiy39IQIwlB9JyzGUW"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="22333914"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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required-field-asterisk"> Name your collection: </label><input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label"> Choose a collection: </label><select id="collections-action-dialog-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 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'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="collections_button" data-ga-action="click" data-ga-label="add"> Add </button><button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="collections_button" data-ga-action="click" data-ga-label="cancel"> Cancel </button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" 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class="article-details" id="article-details">   <header class="heading" id="heading"> <div class="full-view" id="full-view-heading"> <div class="article-citation"> <div class="article-source"> <div class="journal-actions dropdown-block"><button id="full-view-journal-trigger" class="journal-actions-trigger trigger" ref="linksrc=journal_actions_btn" title="The EMBO journal" tabindex="0" aria-controls="full-view-journal" aria-expanded="false" aria-label="Toggle dropdown menu for journal The EMBO journal" data-pinger-ignore> EMBO J </button><div id="full-view-journal" class="journal-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for journal The EMBO journal"><div class="title">Actions</div><div class="content"><ul class="journal-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22EMBO+J%22%5Bjour%5D&sort=date&sort_order=desc" data-href="/?term=%22EMBO+J%22%5Bjour%5D&sort=date&sort_order=desc" 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class="heading-title"> A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis </h1> <div class="inline-authors"> <div class="authors"> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Ara%C3%A7+D&cauthor_id=22333914" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Demet Araç">Demet Araç</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Howard Hughes Medical Institute, Stanford, CA, USA. demeta@stanford.edu" href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Boucard+AA&cauthor_id=22333914" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Antony A Boucard">Antony A Boucard</a><span class="comma">, </span></span><span 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class="in-clipboard-label " hidden> Item in Clipboard </div> </div> <div class="short-view" id="short-view-heading"> <h1 class="heading-title"> A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis </h1> <div class="short-citation"> <span class="authors-list"> <span class="authors-list-item "><span class="full-name">Demet Araç</span><span class="citation-separator"> et al.</span></span> </span> <span class="citation-journal"> EMBO J<span class="citation-separator">.</span> </span> <span class="date"> <time class="citation-year" datetime="2012">2012</time><span class="citation-separator">.</span> </span> </div> <div class="more-article-details-section with-display-settings"> <button class="more-article-details" id="toggle-article-details" data-alt-text="Hide details" ref="linksrc=toggle_article_details" aria-controls="full-article-details" aria-expanded="false" data-fetch-url="/22333914/long-authors/" data-id-prefix=""> <span class="title">Show 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class="full-name" href="/?term=Nguyen+J&cauthor_id=22333914" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jenna Nguyen">Jenna Nguyen</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Soltis+SM&cauthor_id=22333914" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="S Michael Soltis">S Michael Soltis</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=S%C3%BCdhof+TC&cauthor_id=22333914" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Thomas C Südhof">Thomas C Südhof</a><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Brunger+AT&cauthor_id=22333914" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Axel T Brunger">Axel T Brunger</a></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliation </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> Howard Hughes Medical Institute, Stanford, CA, USA. demeta@stanford.edu</li> </ul> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">22333914</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC3321182&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3321182/" data-ga-category="full_text" data-ga-action="PMCID" > PMC3321182 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" 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take" ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format" data-default-format-value="abstract" data-current-format-value="abstract" role="region"><button class="trigger usa-button" title="Change format" data-ga-category="display_options" data-ga-action="display_options_dialog"><span class="button-label">Display options</span></button><div class="dropdown" hidden><div class="title"> Display options </div><div class="content"><div class="format-container"><span class="option-label"> Format </span><select name="format" data-initial-value="abstract" aria-label="Display format" id="inline-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div> <div class="abstract" id="abstract"> <h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> The G protein-coupled receptor (GPCR) Proteolysis Site (GPS) of cell-adhesion GPCRs and polycystic kidney disease (PKD) proteins constitutes a highly conserved autoproteolysis sequence, but its catalytic mechanism remains unknown. Here, we show that unexpectedly the ∼40-residue GPS motif represents an integral part of a much larger ∼320-residue domain that we termed GPCR-Autoproteolysis INducing (GAIN) domain. Crystal structures of GAIN domains from two distantly related cell-adhesion GPCRs revealed a conserved novel fold in which the GPS motif forms five β-strands that are tightly integrated into the overall GAIN domain. The GAIN domain is evolutionarily conserved from tetrahymena to mammals, is the only extracellular domain shared by all human cell-adhesion GPCRs and PKD proteins, and is the locus of multiple human disease mutations. Functionally, the GAIN domain is both necessary and sufficient for autoproteolysis, suggesting an autoproteolytic mechanism whereby the overall GAIN domain fine-tunes the chemical environment in the GPS to catalyse peptide bond hydrolysis. Thus, the GAIN domain embodies a unique, evolutionarily ancient and widespread autoproteolytic fold whose function is likely relevant for GPCR signalling and for multiple human diseases. </p> </div> </div> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" data-ga-category="literature_resources" data-ga-action="disclaimer_link" data-ga-label="under_abstract">PubMed Disclaimer</a> </p> <div class="conflict-of-interest" id="conflict-of-interest"> <h2 class="title"> Conflict of interest statement </h2> <div class="statement"> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors declare that they have no conflict of interest.</p> </div> </div> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="figure-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/ddc3e264ce3c/emboj201226f1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="419" data-image-height="827" data-image-alt="Figure 1" data-pmc-id="PMC3321182" data-figure-id="f1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/8da805c3c55b/emboj201226f1.gif" alt="Figure 1" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="419"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="827"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1 </p> </strong> <div class="figure-caption-contents"><p> Structures of CL1 and BAI3.… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1 </p> </strong> <div class="figure-caption-contents"><p> Structures of CL1 and BAI3. ( <b> A </b> ). Diagram of CL1 and BAI3… </p></div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1 </strong> <div class="figure-caption-contents">Structures of CL1 and BAI3. (<b>A</b>). Diagram of CL1 and BAI3 showing the domains suggested by the SMART protein domain prediction server. No domain is predicted for the stalk region (coloured yellow and light pink). Note that GPS is defined as a separate domain in the Pfam database (magenta). In contrast, our crystal structures (see <b>B</b> and <b>C</b>) now show that the GPS motif is not an autonomously folded domain, but rather an integral part of the GAIN domain. The stalk region is also part of the GAIN domain. The HormR, TM7, lectin, olfactomedin, and thrombospondin motifs are coloured blue, green, cyan, red, and orange, respectively. The boundaries of the crystal structures are indicated with arrows. (<b>B</b>, <b>C</b>) Cartoon representation of the crystal structure of the HormR and GAIN domains of CL1 (PDB accession code 4DLQ) (<b>B</b>) and BAI3 (PDB accession code 4DLO) (<b>C</b>). The HormR domain is coloured blue, the GAIN subdomain A yellow, the GAIN subdomain B light pink, and the GPS motif, which is part of subdomain B, magenta. The cleaved β-strand of CL1 and the corresponding uncleaved β-strand of BAI3 are coloured orange and cyan, respectively. Disulphide bonds and carbohydrates are shown as black and red sticks, respectively. (<b>D</b>) 2<i>mF</i><sub>o</sub>−<i>DF</i><sub>c</sub> electron density map of the indicated residues around the cleavage site in CL1, contoured at 2σ. (<b>E</b>) 2<i>mF</i><sub>o</sub>−<i>DF</i><sub>c</sub> electron density map of the corresponding uncleaved site in BAI3, also contoured at 2σ. (<b>F</b>) Showing the hydrophobic packing interactions between the cleaved β-strand and the surrounding residues in CL1. (<b>G</b>) Showing the hydrogen bonds between the cleaved β-strand and the surrounding residues in CL1. In all panels, the cleavage site in CL1 and the corresponding peptide bond in BAI3 are marked with a black star. (<b>H</b>) The majority of the extracellular regions of CL1 and CL3 remain attached to the cells upon cleavage. HEK293 cells were transfected with full-length CL1 and CL3 constructs. Equal ratio of cell lysates and media were loaded on the gel and immunoblotted for the N-terminal Flag epitope. (<b>I</b>) The cleaved β-strand of the GAIN domain undergoes a conformational change upon autoproteolysis (the direction of the movement is indicated by arrows).</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="figure-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/40f28839c806/emboj201226f2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="427" data-image-height="754" data-image-alt="Figure 2" data-pmc-id="PMC3321182" data-figure-id="f2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/6ede20947fba/emboj201226f2.gif" alt="Figure 2" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="427"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="754"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2 </p> </strong> <div class="figure-caption-contents"><p> The GAIN domain is an… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2 </p> </strong> <div class="figure-caption-contents"><p> The GAIN domain is an autoproteolytic domain. ( <b> A </b> ) Diagram showing the… </p></div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2 </strong> <div class="figure-caption-contents">The GAIN domain is an autoproteolytic domain. (<b>A</b>) Diagram showing the CL1 deletion mutants that we tested in full-length CL1. The constructs were tagged with Flag and Haemagglutinin A (HA) epitopes (grey), both facing the extracellular side. (<b>B</b>) Effect of domain deletions on cleavage of CL1 constructs in HEK293 cells. For the cleavage assay, cell extracts were immunoblotted for the HA epitope. If cleavage at the GPS site occurs, a C-terminal 70 kDa fragment is produced. FL represents full length. (<b>C</b>) Effect of the domain deletions on cell-surface transport of CL1 in HEK293 cells. Transfected HEK293 cells expressing the indicated CL1 proteins were analysed by immunocytochemistry using antibodies to the HA tag; cells were either analysed with or without permeabilization. Cells were visualized by confocal microscopy using an Alexa-488 secondary antibody. (<b>D</b>) A construct encoding only the GAIN domain of CL1 as an Ig-fusion protein is autoproteolysed in transfected HEK293 cells whereas the two autoproteolysis site mutants are not cleaved (blotted for Ig). (<b>E</b>) Schematic domain diagram of GPR56. (<b>F</b>) A construct encoding only the GAIN domain of GPR56 as a myc tagged PDGF receptor transmembrane domain-fusion protein is autoproteolysed whereas the two autoproteolysis site mutants are not cleaved (blotted for myc-epitope).</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="figure-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/c87f2f18c096/emboj201226f3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="480" data-image-height="390" data-image-alt="Figure 3" data-pmc-id="PMC3321182" data-figure-id="f3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/519558090153/emboj201226f3.gif" alt="Figure 3" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="480"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="390"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3 </p> </strong> <div class="figure-caption-contents"><p> The GAIN domain is an… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3 </p> </strong> <div class="figure-caption-contents"><p> The GAIN domain is an ancient domain that exists in primitive organisms. The… </p></div> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3 </strong> <div class="figure-caption-contents">The GAIN domain is an ancient domain that exists in primitive organisms. The structure of the GAIN domain was used to discover this evolutionary relationship. First, BLAST searches were performed to find other GPS motifs. Then, among this group of proteins, the search pattern was extended by including approximately 400 residues upstream of the GPS motif. These sequences were aligned by PROMALS and the secondary structure patterns corresponding to each sequence were predicted by PSIPRED. Finally, the predicted secondary structure patterns were checked against the crystal structure of the GAIN domain and only those that had the same pattern were identified as GAIN domains. (<b>A</b>) Showing the sequence alignment of GPS motifs from evolutionary ancient organisms (top, <i>Tetrahymena thermohila</i> (gi89298346), <i>Dictyostelium discoideum</i> (gi66815909), <i>Monosiga brevicollis</i> (gi16752408), <i>Trichoplax adhaerens</i> (gi19600360), <i>Caenorhabditis elegans</i> (gi11553241)), PKD homologues (middle), and cell-adhesion GPCRs (bottom). The evolutionary relationship between the ancient organisms is described as a tree. The minimum number of GAIN domains in each organism's genome is indicated in parenthesis. The conserved cysteines, tryptophans, and cleavage site residues are highlighted black, magenta, and cyan, respectively. Disease mutations (ADPKD, cancer, and BFPP) are highlighted yellow. The cleavage site is indicated with an arrow. Disulphide bonds are shown as black lines. (<b>B</b>) Predicted consensus secondary structure pattern for representative ancient GAIN domains, cell-adhesion GPCRs, and PKD-related proteins shown in Supplementary Tables S2 and S3.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="figure-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/678aeef7b719/emboj201226f4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="648" data-image-height="427" data-image-alt="Figure 4" data-pmc-id="PMC3321182" data-figure-id="f4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/ea66dda08b3d/emboj201226f4.gif" alt="Figure 4" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="648"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="427"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4 </p> </strong> <div class="figure-caption-contents"><p> BAI3 GAIN domain is functional… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4 </p> </strong> <div class="figure-caption-contents"><p> BAI3 GAIN domain is functional but its autoproteolysis is not required for surface… </p></div> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4 </strong> <div class="figure-caption-contents">BAI3 GAIN domain is functional but its autoproteolysis is not required for surface transport. (<b>A</b>) Immunoblots of the lysates from HEK293 cells transfected with BAI1, BAI2, or BAI3 constructs tagged with mVenus in their C-terminal tails. Sample amounts were adjusted for immunoblotting to obtain comparable signals for BAIs; therefore, unspecific bands exhibit different intensities (black star). Blots were probed with antibodies raised against C-terminal epitopes of BAI1 and BAI3. Only full-length (FL) BAIs (200 kDa) and N-terminally truncated BAIs of unknown physiological relevance (FL<sup>**</sup>) (∼170 kDa) were detected, but no products of autoproteolytic cleavage (expected mass: ∼100 kDa) were observed. (<b>B</b>) Images of non-permeabilized HEK293 cells transfected with mVenus-tagged BAI3 cDNA demonstrate cell-surface membrane localization of uncleaved BAI3 (scale bar=10 μm). (<b>C</b>) Immunoblots of mouse brain lysates and of brain immunoprecipitates (IPs) obtained with the BAI1-specific antibody 11509 (control: IP without 11509) with the antibodies used in (<b>A</b>). A C-terminal cleavage product of 72 kDa was detected.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="4" data-label-slug="figure-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/ea0d0cb85016/emboj201226f5.jpg" itemprop="contentUrl" aria-describedby="figure-caption-4" role="button" data-image-width="484" data-image-height="571" data-image-alt="Figure 5" data-pmc-id="PMC3321182" data-figure-id="f5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-4" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/422da4b54133/emboj201226f5.gif" alt="Figure 5" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="484"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="571"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5 </p> </strong> <div class="figure-caption-contents"><p> Mutagenesis of the CL1 autoproteolysis… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5 </p> </strong> <div class="figure-caption-contents"><p> Mutagenesis of the CL1 autoproteolysis site. ( <b> A </b> ) Close-up view of the… </p></div> </div> <figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5 </strong> <div class="figure-caption-contents">Mutagenesis of the CL1 autoproteolysis site. (<b>A</b>) Close-up view of the cleavage site in CL1 (black star). (<b>B</b>) The corresponding site in uncleaved BAI3 (black star). The colour coding is similar to that in Figure 1, except that the β-strands 12, 13, and the top loop are coloured green, orange, and grey, respectively. Residues involved in autoproteolysis (see mutagenesis experiments) are highlighted black. Water molecules and a sulphate ion are shown as red and cyan spheres, respectively. Hydrogen bonds are shown as black dashes. (<b>C</b>) Results of the cleavage assay of CL1 mutants (same assay as described in Figure 2B). (<b>D</b>) Effect of selected cleavage mutations on cell-surface transport of CL1 in HEK293 cells. Uncleaved, but properly cell-surface localized (i.e., folded), mutants are highlighted black.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="5" data-label-slug="figure-6"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/f1bfd7a9ea19/emboj201226f6.jpg" itemprop="contentUrl" aria-describedby="figure-caption-5" role="button" data-image-width="524" data-image-height="442" data-image-alt="Figure 6" data-pmc-id="PMC3321182" data-figure-id="f6"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-5" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/dae065862c92/emboj201226f6.gif" alt="Figure 6" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="524"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="442"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 6 </p> </strong> <div class="figure-caption-contents"><p> The effect of ADPKD and… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 6 </p> </strong> <div class="figure-caption-contents"><p> The effect of ADPKD and cancer mutations on autoproteolysis. ( <b> A </b> ) The… </p></div> </div> <figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 6 </strong> <div class="figure-caption-contents">The effect of ADPKD and cancer mutations on autoproteolysis. (<b>A</b>) The ADPKD substitution mutations (yellow spheres) and gene conversion mutations (green spheres) in the human <i>PKD1</i> gene; and BFPP substitution mutations (red spheres) in the human <i>GPR56</i> gene are superposed on the structure of the CL1 GAIN domain. The cleavage site is indicated with a black star. (<b>B</b>) Effect of ADPKD mutations on the cleavage of the full-length hPKD1 construct that has an N-terminal GFP and a C-terminal Flag tags. HEK293 cells were transfected with the wild-type and mutant hPKD1 constructs and cell extracts were immunoblotted for the Flag epitope. A C-terminal 130 kDa fragment is produced following autoproteolysis in the GAIN domain. The approximate size of hPKD1 is indicated. The mutants that poorly expressed are labelled with black stars. (<b>C</b>) The cancer substitution mutations (yellow spheres) in the human <i>CL1</i> and <i>CL3</i> genes marked in the structure of the CL1 GAIN domain. (<b>D</b>) Effect of cancer mutations on the cleavage of the full-length rat CL1 and human CL3 that has tags similar to those shown in Figure 2A. Cell extracts were immunoblotted for the HA epitope. A C-terminal 70 kDa fragment is produced following cleavage. FL represents full length.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="6" data-label-slug="figure-7"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/926ffd5a0ec0/emboj201226f7.jpg" itemprop="contentUrl" aria-describedby="figure-caption-6" role="button" data-image-width="417" data-image-height="478" data-image-alt="Figure 7" data-pmc-id="PMC3321182" data-figure-id="f7"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-6" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/95d457e03504/emboj201226f7.gif" alt="Figure 7" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="417"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="478"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 7 </p> </strong> <div class="figure-caption-contents"><p> The GAIN domain of CL1… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 7 </p> </strong> <div class="figure-caption-contents"><p> The GAIN domain of CL1 binds to α-latrotoxin. ( <b> A </b> ) Ig-fusion proteins… </p></div> </div> <figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 7 </strong> <div class="figure-caption-contents">The GAIN domain of CL1 binds to α-latrotoxin. (<b>A</b>) Ig-fusion proteins of CL1 comprising the lectin domain (CL1LEC), the GAIN domain (CL1GAIN), or control (IgC) were expressed in HEK293 cells and purified on protein A sepharose beads along with Ig-fusion proteins of Neurexin-1α and Neurexin-1β (N1α and N1β). Recombinant myc–α-latrotoxin produced in bacteria was added. Proteins were visualized by Coomassie-blue staining (left) or immunoblotting using anti-myc antibody (right). (<b>B</b>) Native gel showing the formation of a complex of CL1-GAIN domain and the 20 ankyrin repeats of α-latrotoxin in a calcium-independent manner. Both proteins were expressed in insect cells as His-tagged proteins, secreted to the media, and purified to >99% purity by affinity tag purification followed by size-exclusion chromatography.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="7" data-label-slug="figure-8"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/a8c09c77548a/emboj201226f8.jpg" itemprop="contentUrl" aria-describedby="figure-caption-7" role="button" data-image-width="420" data-image-height="221" data-image-alt="Figure 8" data-pmc-id="PMC3321182" data-figure-id="f8"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-7" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/8e4c5f26cccb/emboj201226f8.gif" alt="Figure 8" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="420"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="221"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 8 </p> </strong> <div class="figure-caption-contents"><p> The HormR domains of cell-adhesion… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 8 </p> </strong> <div class="figure-caption-contents"><p> The HormR domains of cell-adhesion GPCRs exhibit structural similarity to genuine hormone-binding domains.… </p></div> </div> <figcaption id="figure-caption-7" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 8 </strong> <div class="figure-caption-contents">The HormR domains of cell-adhesion GPCRs exhibit structural similarity to genuine hormone-binding domains. (<b>A</b>) Superposition of the HormR domains of CL1 (blue), BAI3 (grey), and CRFR (green) (PDB ID 3ehu). The structure of the CL1 HormR domain is superposed on the structure of the CRFR HormR domain (green). (<b>B</b>) Binding of a putative hormone (red α-helix) to the CL1 HormR domain based on hormone (corticotrophin releasing factor) binding to CRFR would produce a clash with the GAIN domain. Thus, a conformational change would be required in order to make the putative hormone binding site accessible to the hormone. The colour coding of CL1 is the same as in Figure 1A. Disulphide bonds are shown as black sticks. The disulphide bond close to the hormone binding site is indicated with a red arrow.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="8" data-label-slug="figure-9"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/f7a41760fb61/emboj201226f9.jpg" itemprop="contentUrl" aria-describedby="figure-caption-8" role="button" data-image-width="418" data-image-height="262" data-image-alt="Figure 9" data-pmc-id="PMC3321182" data-figure-id="f9"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-8" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/491a/3321182/61222039f0d7/emboj201226f9.gif" alt="Figure 9" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="418"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="262"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 9 </p> </strong> <div class="figure-caption-contents"><p> The GAIN and HormR domains… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 9 </p> </strong> <div class="figure-caption-contents"><p> The GAIN and HormR domains are in close proximity to GPCR transmembrane helices.… </p></div> </div> <figcaption id="figure-caption-8" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 9 </strong> <div class="figure-caption-contents">The GAIN and HormR domains are in close proximity to GPCR transmembrane helices. The short linker between the GAIN domain and the first GPCR transmembrane helix brings the GAIN and HormR domains close to the transmembrane domain, restricting possible arrangements between the domains. A model of CL1 is shown with a plausible arrangement of the GAIN and HormR domains. The model represents only one of the possible orientations of the GAIN domain with respect to the transmembrane helices. The seven-pass transmembrane domain (orange) was modelled by homology using the crystal structure of the β2 adrenergic GPCR structure (PDB ID 2RH1) (Cherezov et al, 2007; Rosenbaum et al, 2007), and the GAIN and HormR domains were taken from the crystal structure of CL1. The cleavage site is indicated with a black star.</div> </figcaption> </figure> </div> <div class="see-all actions-bar"> <button class="show-more" aria-controls="slides-container" data-ga-category="figure" data-ga-action="show_all"> All figures (9) </button> </div>  <div class="pswp figures-dialog" id="figures-dialog" tabindex="-1" role="dialog" aria-hidden="true" data-image-gallery-uid="article-figures" aria-label="Figures Dialog">  <div class="pswp__bg"></div>  <div class="pswp__scroll-wrap">  <div class="pswp__container"> <div class="pswp__item"></div> <div class="pswp__item"></div> <div class="pswp__item"></div> </div>  <div class="pswp__ui pswp__ui--hidden"> <div class="pswp__top-bar">  <div class="pswp__counter"></div> <button class="pswp__button pswp__button--close" title="Close (Esc)"></button> <button class="pswp__button pswp__button--share" title="Share"></button> <button class="pswp__button pswp__button--fs" title="Toggle fullscreen"></button> <button class="pswp__button pswp__button--zoom" title="Zoom in/out"></button>   <div class="pswp__preloader"> <div class="pswp__preloader__icn"> <div class="pswp__preloader__cut"> <div class="pswp__preloader__donut"></div> </div> </div> </div> </div> <div class="pswp__share-modal pswp__share-modal--hidden pswp__single-tap"> <div class="pswp__share-tooltip"></div> </div> <button class="pswp__button pswp__button--arrow--left" title="Previous (arrow left)"> </button> <button class="pswp__button pswp__button--arrow--right" title="Next (arrow right)"> </button> <div class="pswp__caption"> <div class="pswp__caption__center"></div> </div> </div> </div> </div> <div class="figure-dialog-caption"> <div class="figure-caption-link-container"> <a class="figure-caption-link" href="#">See this image and copyright information in PMC</a> </div> <div class="figure-caption-center" data-expand-title="click to show full caption" data-collapse-title="click to hide full caption"> </div> <button class="figure-caption-toggle-btn" aria-label="show full caption" data-expand-text="show full caption" data-collapse-text="hide full caption">  </button> </div> </div> <div class="linked-articles" id="linked-commentary"> <h2 class="title"> Comment in </h2> <ul class="item-list usa-unstyled-list"> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/22388517/" ref="article_id=22388517&linksrc=comments_link" data-ga-category="comment_correction" data-ga-action="abstract_page_link" data-ga-label="linked-commentary"> A GAIN in understanding autoproteolytic G protein-coupled receptors and polycystic kidney disease proteins. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Tesmer JJ.</span> <span class="docsum-authors short-authors">Tesmer JJ.</span> <span class="docsum-journal-citation full-journal-citation">EMBO J. 2012 Mar 21;31(6):1334-5. doi: 10.1038/emboj.2012.51. 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menu for keyword Animals" tabindex="0" aria-controls="keyword-actions-mesh-terms-1" aria-expanded="false" data-pinger-ignore> Animals </button><div id="keyword-actions-mesh-terms-1" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Animals"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Animals"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Animals"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Animals" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Animals"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Animals"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Animals"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Cell Adhesion / genetics" tabindex="0" aria-controls="keyword-actions-mesh-terms-2" aria-expanded="false" data-pinger-ignore> Cell Adhesion / genetics </button><div id="keyword-actions-mesh-terms-2" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Cell Adhesion / genetics"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Cell+Adhesion%2Fgenetics%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Cell+Adhesion%2Fgenetics%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Cell Adhesion/genetics"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Cell Adhesion / genetics"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Cell+Adhesion" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Cell Adhesion / genetics"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Cell Adhesion/genetics"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Cell Adhesion/genetics"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Cells, Cultured" tabindex="0" aria-controls="keyword-actions-mesh-terms-3" aria-expanded="false" data-pinger-ignore> Cells, Cultured </button><div id="keyword-actions-mesh-terms-3" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Cells, Cultured"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Cells%2C+Cultured%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Cells%2C+Cultured%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Cells, Cultured"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Cells, Cultured"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Cells%2C+Cultured" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Cells, Cultured"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Cells, Cultured"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Cells, Cultured"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Conserved Sequence*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-4" aria-expanded="false" data-pinger-ignore> Conserved Sequence* </button><div id="keyword-actions-mesh-terms-major-4" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Conserved Sequence*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Conserved+Sequence%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Conserved+Sequence%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Conserved Sequence"[MAJR]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Conserved Sequence*"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Conserved+Sequence" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Conserved Sequence*"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Conserved Sequence"[MAJR]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Conserved Sequence"[MAJR]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major" aria-label="Toggle dropdown menu for keyword Evolution, Molecular*" tabindex="0" aria-controls="keyword-actions-mesh-terms-major-5" aria-expanded="false" data-pinger-ignore> Evolution, Molecular* </button><div id="keyword-actions-mesh-terms-major-5" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Evolution, Molecular*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Evolution%2C+Molecular%22%5BMAJR%5D&sort=date&sort_order=desc" data-href="/?term=%22Evolution%2C+Molecular%22%5BMAJR%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Evolution, Molecular"[MAJR]" data-ga-category="search" 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id="keyword-actions-mesh-terms-6" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword HEK293 Cells"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22HEK293+Cells%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22HEK293+Cells%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="HEK293 Cells"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="HEK293 Cells"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=HEK293+Cells" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="HEK293 Cells"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" 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data-ga-action="mesh_term" data-ga-label="Humans"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Humans" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Humans"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Humans"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Humans"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Hydrolysis" tabindex="0" aria-controls="keyword-actions-mesh-terms-8" aria-expanded="false" data-pinger-ignore> Hydrolysis </button><div id="keyword-actions-mesh-terms-8" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Hydrolysis"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Hydrolysis%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Hydrolysis%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Hydrolysis"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Hydrolysis"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Hydrolysis" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Hydrolysis"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Hydrolysis"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Hydrolysis"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Mice" tabindex="0" aria-controls="keyword-actions-mesh-terms-9" aria-expanded="false" data-pinger-ignore> Mice </button><div id="keyword-actions-mesh-terms-9" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Mice"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Mice%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Mice%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Mice"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Mice"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Mice" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Mice"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Mice"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Mice"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Models, Molecular" tabindex="0" aria-controls="keyword-actions-mesh-terms-10" aria-expanded="false" data-pinger-ignore> Models, Molecular </button><div id="keyword-actions-mesh-terms-10" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Models, Molecular"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Models%2C+Molecular%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Models%2C+Molecular%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Models, Molecular"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Models, Molecular"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Models%2C+Molecular" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Models, Molecular"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Models, Molecular"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Models, Molecular"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Molecular Sequence Data" tabindex="0" aria-controls="keyword-actions-mesh-terms-11" aria-expanded="false" data-pinger-ignore> Molecular Sequence Data </button><div id="keyword-actions-mesh-terms-11" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Molecular Sequence Data"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Molecular+Sequence+Data%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Molecular+Sequence+Data%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Molecular Sequence Data"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Molecular Sequence Data"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Molecular+Sequence+Data" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Molecular Sequence Data"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Molecular Sequence Data"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Molecular Sequence Data"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Mutation / genetics" tabindex="0" aria-controls="keyword-actions-mesh-terms-12" aria-expanded="false" data-pinger-ignore> Mutation / genetics </button><div id="keyword-actions-mesh-terms-12" 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data-href="/?term=%22Nerve+Tissue+Proteins%2Fgenetics%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Nerve Tissue Proteins/genetics"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Nerve Tissue Proteins / genetics"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Nerve+Tissue+Proteins" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Nerve Tissue Proteins / genetics"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Nerve Tissue Proteins/genetics"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Nerve Tissue Proteins/genetics"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button 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PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Nerve+Tissue+Proteins" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Nerve Tissue Proteins / metabolism"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Nerve Tissue Proteins/metabolism"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Nerve Tissue Proteins/metabolism"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword Polycystic Kidney Diseases / genetics" tabindex="0" aria-controls="keyword-actions-mesh-terms-15" aria-expanded="false" data-pinger-ignore> Polycystic Kidney Diseases / genetics </button><div id="keyword-actions-mesh-terms-15" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Polycystic Kidney Diseases / genetics"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Polycystic+Kidney+Diseases%2Fgenetics%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Polycystic+Kidney+Diseases%2Fgenetics%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Polycystic Kidney Diseases/genetics"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Polycystic Kidney Diseases / genetics"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Polycystic+Kidney+Diseases" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Polycystic 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class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Polycystic+Kidney+Diseases%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Polycystic+Kidney+Diseases%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Polycystic Kidney Diseases/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Polycystic Kidney Diseases / metabolism"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Polycystic+Kidney+Diseases" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Polycystic Kidney Diseases / metabolism"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Polycystic Kidney Diseases/metabolism"[MeSH]" 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aria-label="Toggle dropdown menu for keyword Receptors, G-Protein-Coupled / metabolism" tabindex="0" aria-controls="keyword-actions-mesh-terms-23" aria-expanded="false" data-pinger-ignore> Receptors, G-Protein-Coupled / metabolism </button><div id="keyword-actions-mesh-terms-23" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Receptors, G-Protein-Coupled / metabolism"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Receptors%2C+G-Protein-Coupled%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Receptors%2C+G-Protein-Coupled%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Receptors, G-Protein-Coupled/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Receptors, G-Protein-Coupled / metabolism"> Search in 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href="/?term=%22Receptors%2C+Peptide%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22Receptors%2C+Peptide%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="Receptors, Peptide/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="Receptors, Peptide / metabolism"> Search in PubMed </a></li><li><a class="search-in-mesh-link dropdown-block-link" ref="linksrc=search_in_mesh_link" href="https://www.ncbi.nlm.nih.gov/mesh?term=Receptors%2C+Peptide" data-ga-category="search_mesh" data-ga-action="mesh_term_link" data-ga-label="Receptors, Peptide / metabolism"> Search in MeSH </a></li><li><a class="add-to-search-link dropdown-block-link" ref="linksrc=add_to_search_link" role="button" data-search-term=""Receptors, Peptide/metabolism"[MeSH]" data-ga-category="search" data-ga-action="add_to_search" data-ga-label=""Receptors, Peptide/metabolism"[MeSH]" href="#"> Add to Search </a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword TRPP Cation Channels / genetics" tabindex="0" aria-controls="keyword-actions-mesh-terms-26" aria-expanded="false" data-pinger-ignore> TRPP Cation Channels / genetics </button><div id="keyword-actions-mesh-terms-26" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword TRPP Cation Channels / genetics"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22TRPP+Cation+Channels%2Fgenetics%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22TRPP+Cation+Channels%2Fgenetics%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="TRPP Cation Channels/genetics"[MeSH]" data-ga-category="search" 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A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis - PubMed