{"corpus_id":8699473,"paper_sha":"729f6f8e1b33c09c41b63a35275b1b6c278ee638","doi":"10.1371/journal.pcbi.1002948","arxiv_id":null,"pmid":23516344,"pmcid":"3597534","mag_id":2166091400,"dblp_id":"journals/ploscb/MehrbodM13","acl_id":null,"title":"Localized Lipid Packing of Transmembrane Domains Impedes Integrin Clustering","year":2013,"publication_date":"2013-03-01","venue":"PLoS Comput. Biol.","journal":{"name":"PLoS Computational Biology","pages":null,"volume":"9"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, Non-U.S. Gov't","Research Support, U.S. Gov't, Non-P.H.S."],"s2_fields_of_study":["Biology","Medicine","Computer Science"],"reference_count":61,"citation_count":39,"influential_citation_count":1,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Animals","mj":false,"ui":"D000818"},{"d":"CHO Cells","mj":false,"ui":"D016466"},{"d":"Cell Membrane","mj":false,"qs":[{"q":"chemistry","mj":true,"ui":"Q000737"},{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D002462"},{"d":"Cricetinae","mj":false,"ui":"D006224"},{"d":"Cricetulus","mj":false,"ui":"D003412"},{"d":"Humans","mj":false,"ui":"D006801"},{"d":"Integrins","mj":false,"qs":[{"q":"chemistry","mj":true,"ui":"Q000737"},{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D016023"},{"d":"Lipid Bilayers","mj":false,"qs":[{"q":"chemistry","mj":true,"ui":"Q000737"},{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D008051"},{"d":"Molecular Dynamics Simulation","mj":false,"ui":"D056004"},{"d":"Protein Multimerization","mj":false,"ui":"D055503"},{"d":"Protein Structure, Tertiary","mj":false,"ui":"D017434"}],"chemicals":[{"n":"Integrins","ui":"D016023","reg":"0"},{"n":"Lipid Bilayers","ui":"D008051","reg":"0"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1002948&type=printable","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/729f6f8e1b33c09c41b63a35275b1b6c278ee638","s2_open_access_license":"CCBY","s2_open_access_status":"GOLD","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Integrin clustering plays a pivotal role in a host of cell functions. Hetero-dimeric integrin adhesion receptors regulate cell migration, survival, and differentiation by communicating signals bidirectionally across the plasma membrane. Thus far, crystallographic structures of integrin components are solved only separately, and for some integrin types. Also, the sequence of interactions that leads to signal transduction remains ambiguous. Particularly, it remains controversial whether the homo-dimerization of integrin transmembrane domains occurs following the integrin activation (i.e. when integrin ectodomain is stretched out) or if it regulates integrin clustering. This study employs molecular dynamics modeling approaches to address these questions in molecular details and sheds light on the crucial effect of the plasma membrane. Conducting a normal mode analysis of the intact αllbβ3 integrin, it is demonstrated that the ectodomain and transmembrane-cytoplasmic domains are connected via a membrane-proximal hinge region, thus merely transmembrane-cytoplasmic domains are modeled. By measuring the free energy change and force required to form integrin homo-oligomers, this study suggests that the β-subunit homo-oligomerization potentially regulates integrin clustering, as opposed to α-subunit, which appears to be a poor regulator for the clustering process. If α-subunits are to regulate the clustering they should overcome a high-energy barrier formed by a stable lipid pack around them. Finally, an outside-in activation-clustering scenario is speculated, explaining how further loading the already-active integrin affects its homo-oligomerization so that focal adhesions grow in size.","claims":[{"public_id":"cl_26007b947432985985e475f8b7e0860a","status":"active","text":"A stable lipid pack around α-subunits creates a high-energy barrier that must be overcome for α-subunits to regulate clustering.","confidence":0.88,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_26007b947432985985e475f8b7e0860a"},{"public_id":"cl_7a94927083fcebf7e3ba27f60ec1e504","status":"active","text":"An outside-in activation-clustering scenario is proposed in which additional loading of already-active integrin promotes homo-oligomerization and growth of focal adhesions.","confidence":0.84,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_7a94927083fcebf7e3ba27f60ec1e504"},{"public_id":"cl_5fd06115d243f82b8c912d80afe944da","status":"active","text":"The ectodomain and transmembrane-cytoplasmic domains of intact αIIbβ3 integrin are connected through a membrane-proximal hinge region, so the transmembrane-cytoplasmic domains can be modeled in isolation.","confidence":0.94,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_5fd06115d243f82b8c912d80afe944da"},{"public_id":"cl_04bfa04e5514e7e7d3ac60cc777ae687","status":"active","text":"β-subunit homo-oligomerization potentially regulates integrin clustering, whereas α-subunit homo-oligomerization appears to be a poor regulator of the clustering process.","confidence":0.91,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_04bfa04e5514e7e7d3ac60cc777ae687"}],"concepts":[{"public_id":"co_05fe88c3c2bf4dcf35eb14405b4851ac","status":"active","name":"membrane-proximal hinge region","description":"A flexible region near the membrane that connects the integrin ectodomain to the transmembrane-cytoplasmic domains.","types":["protein region"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_05fe88c3c2bf4dcf35eb14405b4851ac"},{"public_id":"co_27faa48525dedabed085e2c67417870a","status":"active","name":"stable lipid pack","description":"A tightly packed lipid environment surrounding the integrin α-subunits in the 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