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dc.contributor.authorGee, Elaine Pei-San
dc.contributor.authorIngber, Donald Elliott
dc.contributor.authorStultz, Collin Melveton
dc.date.accessioned2014-03-24T19:46:11Z
dc.date.issued2008
dc.identifier.citationGee, Elaine P. S., Donald E. Ingber, and Collin M. Stultz. 2008. Fibronectin unfolding revisited: Modeling cell traction-mediated unfolding of the tenth type-III repeat. PLoS One 3(6): e2373.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11987420
dc.description.abstractFibronectin polymerization is essential for the development and repair of the extracellular matrix. Consequently, deciphering the mechanism of fibronectin fibril formation is of immense interest. Fibronectin fibrillogenesis is driven by cell-traction forces that mechanically unfold particular modules within fibronectin. Previously, mechanical unfolding of fibronectin has been modeled by applying tensile forces at the N- and C-termini of fibronectin domains; however, physiological loading is likely focused on the solvent-exposed RGD loop in the 10th type-III repeat of fibronectin (10FNIII), which mediates binding to cell-surface integrin receptors. In this work we used steered molecular dynamics to study the mechanical unfolding of 10FNIII under tensile force applied at this RGD site. We demonstrate that mechanically unfolding 10FNIII by pulling at the RGD site requires less work than unfolding by pulling at the N- and C- termini. Moreover, pulling at the N- and C-termini leads to 10FNIII unfolding along several pathways while pulling on the RGD site leads to a single exclusive unfolding pathway that includes a partially unfolded intermediate with exposed hydrophobic N-terminal β-strands – residues that may facilitate fibronectin self-association. Additional mechanical unfolding triggers an essential arginine residue, which is required for high affinity binding to integrins, to move to a position far from the integrin binding site. This cell traction-induced conformational change may promote cell detachment after important partially unfolded kinetic intermediates are formed. These data suggest a novel mechanism that explains how cell-mediated forces promote fibronectin fibrillogenesis and how cell surface integrins detach from newly forming fibrils. This process enables cells to bind and unfold additional fibronectin modules – a method that propagates matrix assembly.en_US
dc.description.sponsorshipEngineering and Applied Sciencesen_US
dc.description.sponsorshipOther Research Uniten_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0002373en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3494&itool=Abstract-nondef&uid=19020673&nlmid=101285081&db=pubmed&url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19020673en_US
dash.licenseLAA
dc.titleFibronectin Unfolding Revisited: Modeling Cell Traction-Mediated Unfolding of the Tenth Type-III Repeaten_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPlos Oneen_US
dash.depositing.authorIngber, Donald Elliott
dc.date.available2014-03-24T19:46:11Z
dc.identifier.doi10.1371/journal.pone.0002373*
dash.contributor.affiliatedGee, Elaine Pei-San
dash.contributor.affiliatedStultz, Collin
dash.contributor.affiliatedIngber, Donald


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