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Molecular dynamics simulations reveal how vinculin refolds partially unfolded talin rod helices to stabilize them against mechanical force
Vinculin binds to specific sites of mechanically unfolded talin rod domains to reinforce the coupling of the cell's exterior to its force generation machinery. Force-dependent vinculin-talin complexation and dissociation was previously observed as contraction or extension of the unfolded talin...
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Published in: | PLoS computational biology 2024-08, Vol.20 (8), p.e1012341 |
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description | Vinculin binds to specific sites of mechanically unfolded talin rod domains to reinforce the coupling of the cell's exterior to its force generation machinery. Force-dependent vinculin-talin complexation and dissociation was previously observed as contraction or extension of the unfolded talin domains respectively using magnetic tweezers. However, the structural mechanism underlying vinculin recognition of unfolded vinculin binding sites (VBSs) in talin remains unknown. Using molecular dynamics simulations, we demonstrate that a VBS dynamically refolds under force, and that vinculin can recognize and bind to partially unfolded VBS states. Vinculin binding enables refolding of the mechanically strained VBS and stabilizes its folded α-helical conformation, providing resistance against mechanical stress. Together, these results provide an understanding of a recognition mechanism of proteins unfolded by force and insight into the initial moments of how vinculin binds unfolded talin rod domains during the assembly of this mechanosensing meshwork. |
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Force-dependent vinculin-talin complexation and dissociation was previously observed as contraction or extension of the unfolded talin domains respectively using magnetic tweezers. However, the structural mechanism underlying vinculin recognition of unfolded vinculin binding sites (VBSs) in talin remains unknown. Using molecular dynamics simulations, we demonstrate that a VBS dynamically refolds under force, and that vinculin can recognize and bind to partially unfolded VBS states. Vinculin binding enables refolding of the mechanically strained VBS and stabilizes its folded α-helical conformation, providing resistance against mechanical stress. Together, these results provide an understanding of a recognition mechanism of proteins unfolded by force and insight into the initial moments of how vinculin binds unfolded talin rod domains during the assembly of this mechanosensing meshwork.</description><identifier>ISSN: 1553-7358</identifier><identifier>ISSN: 1553-734X</identifier><identifier>EISSN: 1553-7358</identifier><identifier>DOI: 10.1371/journal.pcbi.1012341</identifier><identifier>PMID: 39110765</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Binding Sites ; Biology and Life Sciences ; Humans ; Molecular dynamics ; Molecular Dynamics Simulation ; Physical Sciences ; Protein Binding ; Protein Folding ; Protein Unfolding ; Proteins ; Research and Analysis Methods ; Simulation methods ; Stress, Mechanical ; Talin - chemistry ; Talin - metabolism ; Vinculin - chemistry ; Vinculin - metabolism</subject><ispartof>PLoS computational biology, 2024-08, Vol.20 (8), p.e1012341</ispartof><rights>Copyright: © 2024 Mykuliak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2024 Public Library of Science</rights><rights>2024 Mykuliak et al 2024 Mykuliak et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c489t-2404928348b4b58a3831ba792ab7f0fc5b593c9862b5d346a051cd1ab09e0b763</cites><orcidid>0000-0002-2522-9907 ; 0000-0002-3438-2807 ; 0000-0002-9357-1480</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333002/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333002/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,37013,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39110765$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kasson, Peter M.</contributor><creatorcontrib>Mykuliak, Vasyl V</creatorcontrib><creatorcontrib>Rahikainen, Rolle</creatorcontrib><creatorcontrib>Ball, Neil J</creatorcontrib><creatorcontrib>Bussi, Giovanni</creatorcontrib><creatorcontrib>Goult, Benjamin T</creatorcontrib><creatorcontrib>Hytönen, Vesa P</creatorcontrib><title>Molecular dynamics simulations reveal how vinculin refolds partially unfolded talin rod helices to stabilize them against mechanical force</title><title>PLoS computational biology</title><addtitle>PLoS Comput Biol</addtitle><description>Vinculin binds to specific sites of mechanically unfolded talin rod domains to reinforce the coupling of the cell's exterior to its force generation machinery. Force-dependent vinculin-talin complexation and dissociation was previously observed as contraction or extension of the unfolded talin domains respectively using magnetic tweezers. However, the structural mechanism underlying vinculin recognition of unfolded vinculin binding sites (VBSs) in talin remains unknown. Using molecular dynamics simulations, we demonstrate that a VBS dynamically refolds under force, and that vinculin can recognize and bind to partially unfolded VBS states. Vinculin binding enables refolding of the mechanically strained VBS and stabilizes its folded α-helical conformation, providing resistance against mechanical stress. Together, these results provide an understanding of a recognition mechanism of proteins unfolded by force and insight into the initial moments of how vinculin binds unfolded talin rod domains during the assembly of this mechanosensing meshwork.</description><subject>Binding Sites</subject><subject>Biology and Life Sciences</subject><subject>Humans</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Physical Sciences</subject><subject>Protein Binding</subject><subject>Protein Folding</subject><subject>Protein Unfolding</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Simulation methods</subject><subject>Stress, Mechanical</subject><subject>Talin - chemistry</subject><subject>Talin - metabolism</subject><subject>Vinculin - chemistry</subject><subject>Vinculin - metabolism</subject><issn>1553-7358</issn><issn>1553-734X</issn><issn>1553-7358</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNqVksuO0zAUhiMEYoaBN0DIEhtYtNhxbMcrNBpxqTSAxGVtHTtO68qxS-wUyiPw1LjTMppKbFAWsf5851Ny8lfVU4LnhAryah2nMYCfb4x2c4JJTRtyrzonjNGZoKy9f-d8Vj1KaY1xOUr-sDqjkhAsODuvfn-I3prJw4i6XYDBmYSSG0qQXQwJjXZrwaNV_IG2LhTQhZL10XcJbWDMDrzfoSnsE9uhDDdA7NDKemdsQjmilEE7735ZlFd2QLAEF1JGgzUrCM4UfR9HYx9XD3rwyT453i-qb2_ffL16P7v-9G5xdXk9M00r86xucCPrljatbjRrgbaUaBCyBi163BummaRGtrzWrKMNB8yI6QhoLC3WgtOLanHwdhHWajO6AcadiuDUTRDHpdp_mPFW0Z7XrGF9KyVvsADAuChETzluay1Fcb0-uDaTHmxnbMgj-BPp6ZPgVmoZt4oQSinGdTG8OBrG-H2yKavBJWO9h2DjlBTFEnNKJG8L-vyALqG8mys7L0qzx9VliwXmRNSkUPN_UOXqbPm7Mdjelfxk4OXJQGGy_ZmXMKWkFl8-_wf78ZRtDqwZY0qlNLdrIVjtK6yOFVb7CqtjhcvYs7srvR3621n6B0u478M</recordid><startdate>20240807</startdate><enddate>20240807</enddate><creator>Mykuliak, Vasyl V</creator><creator>Rahikainen, Rolle</creator><creator>Ball, Neil J</creator><creator>Bussi, Giovanni</creator><creator>Goult, Benjamin T</creator><creator>Hytönen, Vesa P</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-2522-9907</orcidid><orcidid>https://orcid.org/0000-0002-3438-2807</orcidid><orcidid>https://orcid.org/0000-0002-9357-1480</orcidid></search><sort><creationdate>20240807</creationdate><title>Molecular dynamics simulations reveal how vinculin refolds partially unfolded talin rod helices to stabilize them against mechanical force</title><author>Mykuliak, Vasyl V ; Rahikainen, Rolle ; Ball, Neil J ; Bussi, Giovanni ; Goult, Benjamin T ; Hytönen, Vesa P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c489t-2404928348b4b58a3831ba792ab7f0fc5b593c9862b5d346a051cd1ab09e0b763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Binding Sites</topic><topic>Biology and Life Sciences</topic><topic>Humans</topic><topic>Molecular dynamics</topic><topic>Molecular Dynamics Simulation</topic><topic>Physical Sciences</topic><topic>Protein Binding</topic><topic>Protein Folding</topic><topic>Protein Unfolding</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>Simulation methods</topic><topic>Stress, Mechanical</topic><topic>Talin - chemistry</topic><topic>Talin - metabolism</topic><topic>Vinculin - chemistry</topic><topic>Vinculin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mykuliak, Vasyl V</creatorcontrib><creatorcontrib>Rahikainen, Rolle</creatorcontrib><creatorcontrib>Ball, Neil J</creatorcontrib><creatorcontrib>Bussi, Giovanni</creatorcontrib><creatorcontrib>Goult, Benjamin T</creatorcontrib><creatorcontrib>Hytönen, Vesa P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PLoS computational biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mykuliak, Vasyl V</au><au>Rahikainen, Rolle</au><au>Ball, Neil J</au><au>Bussi, Giovanni</au><au>Goult, Benjamin T</au><au>Hytönen, Vesa P</au><au>Kasson, Peter M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular dynamics simulations reveal how vinculin refolds partially unfolded talin rod helices to stabilize them against mechanical force</atitle><jtitle>PLoS computational biology</jtitle><addtitle>PLoS Comput Biol</addtitle><date>2024-08-07</date><risdate>2024</risdate><volume>20</volume><issue>8</issue><spage>e1012341</spage><pages>e1012341-</pages><issn>1553-7358</issn><issn>1553-734X</issn><eissn>1553-7358</eissn><abstract>Vinculin binds to specific sites of mechanically unfolded talin rod domains to reinforce the coupling of the cell's exterior to its force generation machinery. Force-dependent vinculin-talin complexation and dissociation was previously observed as contraction or extension of the unfolded talin domains respectively using magnetic tweezers. However, the structural mechanism underlying vinculin recognition of unfolded vinculin binding sites (VBSs) in talin remains unknown. Using molecular dynamics simulations, we demonstrate that a VBS dynamically refolds under force, and that vinculin can recognize and bind to partially unfolded VBS states. Vinculin binding enables refolding of the mechanically strained VBS and stabilizes its folded α-helical conformation, providing resistance against mechanical stress. 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subjects | Binding Sites Biology and Life Sciences Humans Molecular dynamics Molecular Dynamics Simulation Physical Sciences Protein Binding Protein Folding Protein Unfolding Proteins Research and Analysis Methods Simulation methods Stress, Mechanical Talin - chemistry Talin - metabolism Vinculin - chemistry Vinculin - metabolism |
title | Molecular dynamics simulations reveal how vinculin refolds partially unfolded talin rod helices to stabilize them against mechanical force |
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