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This pre-print is available under a Creative Commons License (Attribution 4.0 International), CC BY 4.0, as described at http://creativecommons.org/licenses/by/4.0/" /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Description" content="Integrin binding to extracellular matrix proteins is regulated by conformational transitions from closed, low affinity states to open, high affinity states. However, the pathways of integrin conformational activation remain incompletely understood. Here, by combining all-atom molecular dynamics simulation, coarse-graining, heterogeneous elastic network modeling, and experimental ligand binding measurements, we test the effect of integrin β mutations that destabilize the closed conformation. Our results support a “deadbolt” model of integrin activation, where extension of the headpiece is not coupled to leg separation, consistent with recent cryo-EM reconstructions of integrin intermediates. Moreover, our results are inconsistent with a “switchblade-like” mechanism. The data show that locally correlated atomistic motions are likely responsible for extension of integrin headpiece before separation of transmembrane legs, without persistence of these correlations across the entire protein. By combining modeling and simulation with experiment, this study provides new insight into the structural basis of full-length integrin activation." /> <meta name="DC.Contributor" content="Tamara C. Bidone" /> <meta name="DC.Contributor" content="Anirban Polley" /> <meta name="DC.Contributor" content="Aleksander Durumeric" /> <meta name="DC.Contributor" content="Tristan Driscoll" /> <meta name="DC.Contributor" content="Daniel Iwamoto" /> <meta name="DC.Contributor" content="David Calderwood" /> <meta name="DC.Contributor" content="Martin A. Schwartz" /> <meta name="DC.Contributor" content="Gregory A Voth" /> <meta name="article:published_time" content="2017-10-15" /> <meta name="article:section" content="New Results" /> <meta name="citation_title" content="New Insights into the Conformational Activation of Full-Length Integrin" /> <meta name="citation_abstract" lang="en" content="<h3>ABSTRACT</h3> <p>Integrin binding to extracellular matrix proteins is regulated by conformational transitions from closed, low affinity states to open, high affinity states. However, the pathways of integrin conformational activation remain incompletely understood. Here, by combining all-atom molecular dynamics simulation, coarse-graining, heterogeneous elastic network modeling, and experimental ligand binding measurements, we test the effect of integrin β mutations that destabilize the closed conformation. Our results support a “deadbolt” model of integrin activation, where extension of the headpiece is not coupled to leg separation, consistent with recent cryo-EM reconstructions of integrin intermediates. Moreover, our results are inconsistent with a “switchblade-like” mechanism. The data show that locally correlated atomistic motions are likely responsible for extension of integrin headpiece before separation of transmembrane legs, without persistence of these correlations across the entire protein. By combining modeling and simulation with experiment, this study provides new insight into the structural basis of full-length integrin activation.</p>" /> <meta name="citation_journal_title" content="bioRxiv" /> <meta name="citation_publisher" content="Cold Spring Harbor Laboratory" /> <meta name="citation_publication_date" content="2017/01/01" /> <meta name="citation_mjid" content="biorxiv;203661v1" /> <meta name="citation_id" content="203661v1" /> <meta name="citation_public_url" content="https://www.biorxiv.org/content/10.1101/203661v1" /> <meta name="citation_abstract_html_url" content="https://www.biorxiv.org/content/10.1101/203661v1.abstract" /> <meta name="citation_full_html_url" content="https://www.biorxiv.org/content/10.1101/203661v1.full" /> <meta name="citation_pdf_url" content="https://www.biorxiv.org/content/biorxiv/early/2017/10/15/203661.full.pdf" /> <meta name="citation_doi" content="10.1101/203661" /> <meta name="citation_num_pages" content="26" /> <meta name="citation_article_type" content="Article" /> <meta name="citation_section" content="New Results" /> <meta name="citation_firstpage" content="203661" /> <meta name="citation_author" content="Tamara C. Bidone" /> <meta name="citation_author_institution" content="Department of Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago" /> <meta name="citation_author" content="Anirban Polley" /> <meta name="citation_author_institution" content="Department of Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago" /> <meta name="citation_author" content="Aleksander Durumeric" /> <meta name="citation_author_institution" content="Department of Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0001-5476-4493" /> <meta name="citation_author" content="Tristan Driscoll" /> <meta name="citation_author_institution" content="Departments of Cell Biology and Biomedical Engineering, Yale University" /> <meta name="citation_author" content="Daniel Iwamoto" /> <meta name="citation_author_institution" content="Department of Pharmacology, Yale University" /> <meta name="citation_author" content="David Calderwood" /> <meta name="citation_author_institution" content="Department of Pharmacology, Yale University" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0002-0791-4142" /> <meta name="citation_author" content="Martin A. 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Biol. 7: e1001086." /> <meta name="twitter:title" content="New Insights into the Conformational Activation of Full-Length Integrin" /> <meta name="twitter:site" content="@biorxivpreprint" /> <meta name="twitter:card" content="summary" /> <meta name="twitter:image" content="https://www.biorxiv.org/sites/default/files/images/biorxiv_logo_homepage7-5-small.png" /> <meta name="twitter:description" content="Integrin binding to extracellular matrix proteins is regulated by conformational transitions from closed, low affinity states to open, high affinity states. However, the pathways of integrin conformational activation remain incompletely understood. Here, by combining all-atom molecular dynamics simulation, coarse-graining, heterogeneous elastic network modeling, and experimental ligand binding measurements, we test the effect of integrin β mutations that destabilize the closed conformation. Our results support a “deadbolt” model of integrin activation, where extension of the headpiece is not coupled to leg separation, consistent with recent cryo-EM reconstructions of integrin intermediates. Moreover, our results are inconsistent with a “switchblade-like” mechanism. The data show that locally correlated atomistic motions are likely responsible for extension of integrin headpiece before separation of transmembrane legs, without persistence of these correlations across the entire protein. By combining modeling and simulation with experiment, this study provides new insight into the structural basis of full-length integrin activation." /> <meta name="og-title" property="og:title" content="New Insights into the Conformational Activation of Full-Length Integrin" /> <meta name="og-url" property="og:url" content="https://www.biorxiv.org/content/10.1101/203661v1" /> <meta name="og-site-name" property="og:site_name" content="bioRxiv" /> <meta name="og-description" property="og:description" content="Integrin binding to extracellular matrix proteins is regulated by conformational transitions from closed, low affinity states to open, high affinity states. However, the pathways of integrin conformational activation remain incompletely understood. Here, by combining all-atom molecular dynamics simulation, coarse-graining, heterogeneous elastic network modeling, and experimental ligand binding measurements, we test the effect of integrin β mutations that destabilize the closed conformation. Our results support a “deadbolt” model of integrin activation, where extension of the headpiece is not coupled to leg separation, consistent with recent cryo-EM reconstructions of integrin intermediates. Moreover, our results are inconsistent with a “switchblade-like” mechanism. The data show that locally correlated atomistic motions are likely responsible for extension of integrin headpiece before separation of transmembrane legs, without persistence of these correlations across the entire protein. By combining modeling and simulation with experiment, this study provides new insight into the structural basis of full-length integrin activation." /> <meta name="og-type" property="og:type" content="article" /> <meta name="og-image" property="og:image" content="https://www.biorxiv.org/sites/default/files/images/biorxiv_logo_homepage7-5-small.png" /> <meta name="citation_date" content="2017-10-15" /> <link rel="alternate" type="application/vnd.ms-powerpoint" title="Powerpoint" href="/content/10.1101/203661v1.ppt" /> <meta name="description" content="bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution" /> <meta name="generator" content="Drupal 7 (http://drupal.org)" /> <link rel="canonical" href="https://www.biorxiv.org/content/10.1101/203661v1" /> <link rel="shortlink" href="https://www.biorxiv.org/node/62010" /> <title>New Insights into the Conformational Activation of Full-Length Integrin | bioRxiv</title> 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data-apath="/biorxiv/early/2017/10/15/203661.atom" data-hw-author-tooltip-instance="highwire_author_tooltip"><div class="highwire-cite highwire-cite-highwire-article highwire-citation-biorxiv-article-top clearfix has-author-tooltip" > <span class="biorxiv-article-type"> New Results </span> <h1 class="highwire-cite-title" id="page-title">New Insights into the Conformational Activation of Full-Length Integrin</h1> <div class="highwire-cite-authors" ><span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0"><span class="nlm-given-names">Tamara C.</span> <span class="nlm-surname">Bidone</span></span>, <span class="highwire-citation-author" data-delta="1"><span class="nlm-given-names">Anirban</span> <span class="nlm-surname">Polley</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="2"><a href="http://orcid.org/0000-0001-5476-4493" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Aleksander</span> <span class="nlm-surname">Durumeric</span></span>, <span class="highwire-citation-author" data-delta="3"><span class="nlm-given-names">Tristan</span> <span class="nlm-surname">Driscoll</span></span>, <span class="highwire-citation-author" data-delta="4"><span class="nlm-given-names">Daniel</span> <span class="nlm-surname">Iwamoto</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="5"><a href="http://orcid.org/0000-0002-0791-4142" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">David</span> <span class="nlm-surname">Calderwood</span></span>, <span class="highwire-citation-author" data-delta="6"><span class="nlm-given-names">Martin A.</span> <span class="nlm-surname">Schwartz</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="7"><a href="http://orcid.org/0000-0002-3267-6748" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Gregory A</span> <span class="nlm-surname">Voth</span></span></span></div> <div class="highwire-cite-metadata" ><span class="highwire-cite-metadata-doi highwire-cite-metadata"><span class="label">doi:</span> https://doi.org/10.1101/203661 </span></div> </div> <div id="hw-article-author-popups-node-62010--2987805968" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">Tamara C. Bidone </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago</span>, 5735 S. Ellis Ave., Chicago, Illinois 60637, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Tamara%2BC.%2BBidone%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Bidone%20TC&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3ATamara%2BC.%2BBidone%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">Anirban Polley </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago</span>, 5735 S. Ellis Ave., Chicago, Illinois 60637, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Anirban%2BPolley%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Polley%20A&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AAnirban%2BPolley%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-2"><div class="author-tooltip-name">Aleksander Durumeric </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago</span>, 5735 S. Ellis Ave., Chicago, Illinois 60637, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Aleksander%2BDurumeric%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Durumeric%20A&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AAleksander%2BDurumeric%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0001-5476-4493" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Aleksander Durumeric</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">Tristan Driscoll </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>3</span><span class='nlm-institution'>Departments of Cell Biology and Biomedical Engineering, Yale University</span>, New Haven, Connecticut 06511, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Tristan%2BDriscoll%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Driscoll%20T&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3ATristan%2BDriscoll%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-4"><div class="author-tooltip-name">Daniel Iwamoto </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>4</span><span class='nlm-institution'>Department of Pharmacology, Yale University</span>, New Haven, Connecticut 06511, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Daniel%2BIwamoto%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Iwamoto%20D&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3ADaniel%2BIwamoto%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-5"><div class="author-tooltip-name">David Calderwood </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>4</span><span class='nlm-institution'>Department of Pharmacology, Yale University</span>, New Haven, Connecticut 06511, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=David%2BCalderwood%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Calderwood%20D&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3ADavid%2BCalderwood%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-0791-4142" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for David Calderwood</a></li></ul></div><div class="author-tooltip-6"><div class="author-tooltip-name">Martin A. Schwartz </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>2</span><span class='nlm-institution'>Yale Cardiovascular Research Center and Department of Internal Medicine (Section of Cardiovascular Medicine)</span></div><div class='author-affiliation'><span class='nlm-sup'>3</span><span class='nlm-institution'>Departments of Cell Biology and Biomedical Engineering, Yale University</span>, New Haven, Connecticut 06511, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Martin%2BA.%2BSchwartz%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Schwartz%20MA&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AMartin%2BA.%2BSchwartz%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-7"><div class="author-tooltip-name">Gregory A Voth </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago</span>, 5735 S. Ellis Ave., Chicago, Illinois 60637, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Gregory%2BA%2BVoth%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Voth%20GA&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AGregory%2BA%2BVoth%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link"><a href="http://orcid.org/0000-0002-3267-6748" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Gregory A Voth</a></li><li class="author-corresp-email-link last"><span>For correspondence: <a href="mailto:gavoth@uchicago.edu" class="" data-icon-position="" data-hide-link-title="0">gavoth@uchicago.edu</a></span></li></ul></div></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-panel-tabs pane-panels-ajax-tab-tabs" > <div class="pane-content"> <div class="item-list"><ul class="tabs inline panels-ajax-tab"><li class="first"><a href="/content/10.1101/203661v1" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_art" data-target-id="highwire_article_tabs" data-entity-context="node:62010" data-trigger="" data-url-enabled="1">Abstract</a><a href="/panels_ajax_tab/biorxiv_tab_art/node:62010/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/203661v1.full-text" class="panels-ajax-tab-tab" data-panel-name="article_tab_full_text" data-target-id="highwire_article_tabs" data-entity-context="node:62010" data-trigger="full-text" data-url-enabled="1">Full Text</a><a href="/panels_ajax_tab/article_tab_full_text/node:62010/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/203661v1.article-info" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_info" data-target-id="highwire_article_tabs" data-entity-context="node:62010" data-trigger="article-info" data-url-enabled="1">Info/History</a><a href="/panels_ajax_tab/biorxiv_tab_info/node:62010/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/203661v1.article-metrics" class="panels-ajax-tab-tab" data-panel-name="article_tab_metrics" data-target-id="highwire_article_tabs" data-entity-context="node:62010" data-trigger="article-metrics" data-url-enabled="1">Metrics</a><a href="/panels_ajax_tab/article_tab_metrics/node:62010/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li class="last"><a href="/content/10.1101/203661v1.full.pdf+html" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_pdf" data-target-id="highwire_article_tabs" data-entity-context="node:62010" data-trigger="full.pdf+html" data-url-enabled="1"><i class="icon-file-alt"></i> Preview PDF</a><a href="/panels_ajax_tab/biorxiv_tab_pdf/node:62010/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li></ul></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-panel-tabs-container" > <div class="pane-content"> <div data-panels-ajax-tab-preloaded="biorxiv_tab_art" id="panels-ajax-tab-container-highwire_article_tabs" class="panels-ajax-tab-container"><div class="panels-ajax-tab-loading" style ="display:none"><img class="loading" src="https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif" alt="Loading" title="Loading" /></div><div class="panels-ajax-tab-wrap-biorxiv_tab_art"><div class="panel-display panel-1col clearfix" > <div class="panel-panel panel-col"> <div><div class="panel-pane pane-highwire-markup" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" data-highwire-cite-ref-tooltip-instance="highwire_reflinks_tooltip" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article abstract-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2 class="">ABSTRACT</h2><p id="p-3">Integrin binding to extracellular matrix proteins is regulated by conformational transitions from closed, low affinity states to open, high affinity states. However, the pathways of integrin conformational activation remain incompletely understood. Here, by combining all-atom molecular dynamics simulation, coarse-graining, heterogeneous elastic network modeling, and experimental ligand binding measurements, we test the effect of integrin β mutations that destabilize the closed conformation. Our results support a “deadbolt” model of integrin activation, where extension of the headpiece is not coupled to leg separation, consistent with recent cryo-EM reconstructions of integrin intermediates. Moreover, our results are inconsistent with a “switchblade-like” mechanism. The data show that locally correlated atomistic motions are likely responsible for extension of integrin headpiece before separation of transmembrane legs, without persistence of these correlations across the entire protein. By combining modeling and simulation with experiment, this study provides new insight into the structural basis of full-length integrin activation.</p></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-biorxiv-copyright" > <div class="pane-content"> <div class="field field-name-field-highwire-copyright field-type-text field-label-inline clearfix"><div class="field-label">Copyright </div><div class="field-items"><div class="field-item even">The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.<span class="license-type"> It is made available under a <a href="http://creativecommons.org/licenses/by/4.0/" class="" data-icon-position="" data-hide-link-title="0">CC-BY 4.0 International license</a>.</span></div></div></div> </div> </div> </div> </div> </div> </div></div> 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class="highwire-cite-title" > <div class="highwire-cite-title">New Insights into the Conformational Activation of Full-Length Integrin</div> </div> <div class="highwire-cite-authors" ><span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0"><span class="nlm-given-names">Tamara C.</span> <span class="nlm-surname">Bidone</span></span>, <span class="highwire-citation-author" data-delta="1"><span class="nlm-given-names">Anirban</span> <span class="nlm-surname">Polley</span></span>, <span class="highwire-citation-author" data-delta="2"><span class="nlm-given-names">Aleksander</span> <span class="nlm-surname">Durumeric</span></span>, <span class="highwire-citation-author" data-delta="3"><span class="nlm-given-names">Tristan</span> <span class="nlm-surname">Driscoll</span></span>, <span class="highwire-citation-author" data-delta="4"><span class="nlm-given-names">Daniel</span> <span class="nlm-surname">Iwamoto</span></span>, <span class="highwire-citation-author" data-delta="5"><span class="nlm-given-names">David</span> <span class="nlm-surname">Calderwood</span></span>, <span class="highwire-citation-author" data-delta="6"><span class="nlm-given-names">Martin A.</span> <span class="nlm-surname">Schwartz</span></span>, <span class="highwire-citation-author" data-delta="7"><span class="nlm-given-names">Gregory A</span> <span class="nlm-surname">Voth</span></span></span></div> <div class="highwire-cite-metadata" ><span class="highwire-cite-metadata-journal highwire-cite-metadata">bioRxiv </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">203661; </span><span class="highwire-cite-metadata-doi highwire-cite-metadata"><span class="doi_label">doi:</span> https://doi.org/10.1101/203661 </span></div> </div> </div> </div> </div> </div> </div> <div class="panel-panel grid-12 panel-region-content"> <div class="inside"><div class="panel-pane pane-highwire-article-clipboard-copy" > <div 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