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dc.contributor.authorPirani, Alnoor
dc.contributor.authorVinogradova, Maia V.
dc.contributor.authorCurmi, Paul M.
dc.contributor.authorKing, William A.
dc.contributor.authorFletterick, Robert J.
dc.contributor.authorCraig, Roger W.
dc.contributor.authorTobacman, Larry S.
dc.contributor.authorXu, Chen
dc.contributor.authorHatch, Victoria
dc.contributor.authorLehman, William
dc.date2022-08-11T08:08:12.000
dc.date.accessioned2022-08-23T15:46:00Z
dc.date.available2022-08-23T15:46:00Z
dc.date.issued2006-02-14
dc.date.submitted2010-10-06
dc.identifier.citationJ Mol Biol. 2006 Mar 31;357(3):707-17. Epub 2006 Jan 13. <a href="http://dx.doi.org/10.1016/j.jmb.2005.12.050">Link to article on publisher's site</a>
dc.identifier.issn0022-2836 (Linking)
dc.identifier.doi10.1016/j.jmb.2005.12.050
dc.identifier.pmid16469331
dc.identifier.urihttp://hdl.handle.net/20.500.14038/27661
dc.description.abstractContraction of striated muscles is regulated by tropomyosin strands that run continuously along actin-containing thin filaments. Tropomyosin blocks myosin-binding sites on actin in resting muscle and unblocks them during Ca2+-activation. This steric effect controls myosin-crossbridge cycling on actin that drives contraction. Troponin, bound to the thin filaments, couples Ca2+-concentration changes to the movement of tropomyosin. Ca2+-free troponin is thought to trap tropomyosin in the myosin-blocking position, while this constraint is released after Ca2+-binding. Although the location and movements of tropomyosin are well known, the structural organization of troponin on thin filaments is not. Its mechanism of action therefore remains uncertain. To determine the organization of troponin on the thin filament, we have constructed atomic models of low and high-Ca2+ states based on crystal structures of actin, tropomyosin and the "core domain" of troponin, and constrained by distances between filament components and by their location in electron microscopy (EM) reconstructions. Alternative models were also built where troponin was systematically repositioned or reoriented on actin. The accuracy of the different models was evaluated by determining how well they corresponded to EM images. While the initial low and high-Ca2+ models fitted the data precisely, the alternatives did not, suggesting that the starting models best represented the correct structures. Thin filament reconstructions were generated from the EM data using these starting models as references. In addition to showing the core domain of troponin, the reconstructions showed additional detail not present in the starting models. We attribute this to an extension of TnI linking the troponin core domain to actin at low (but not at high) Ca2+, thereby trapping tropomyosin in the OFF-state. The bulk of the core domain of troponin appears not to move significantly on actin, regardless of Ca2+ level. Our observations suggest a simple model for muscle regulation in which troponin affects the charge balance on actin and hence tropomyosin position.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=16469331&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1016/j.jmb.2005.12.050
dc.subjectActins
dc.subjectCalcium
dc.subjectHumans
dc.subjectMicrofilament Proteins
dc.subject*Models, Molecular
dc.subjectProtein Structure, Tertiary
dc.subjectSoftware
dc.subjectTropomyosin
dc.subjectTroponin
dc.subjectCell Biology
dc.titleAn atomic model of the thin filament in the relaxed and Ca2+-activated states
dc.typeArticle
dc.source.journaltitleJournal of molecular biology
dc.source.volume357
dc.source.issue3
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/craig/14
dc.identifier.contextkey1594913
html.description.abstract<p>Contraction of striated muscles is regulated by tropomyosin strands that run continuously along actin-containing thin filaments. Tropomyosin blocks myosin-binding sites on actin in resting muscle and unblocks them during Ca2+-activation. This steric effect controls myosin-crossbridge cycling on actin that drives contraction. Troponin, bound to the thin filaments, couples Ca2+-concentration changes to the movement of tropomyosin. Ca2+-free troponin is thought to trap tropomyosin in the myosin-blocking position, while this constraint is released after Ca2+-binding. Although the location and movements of tropomyosin are well known, the structural organization of troponin on thin filaments is not. Its mechanism of action therefore remains uncertain. To determine the organization of troponin on the thin filament, we have constructed atomic models of low and high-Ca2+ states based on crystal structures of actin, tropomyosin and the "core domain" of troponin, and constrained by distances between filament components and by their location in electron microscopy (EM) reconstructions. Alternative models were also built where troponin was systematically repositioned or reoriented on actin. The accuracy of the different models was evaluated by determining how well they corresponded to EM images. While the initial low and high-Ca2+ models fitted the data precisely, the alternatives did not, suggesting that the starting models best represented the correct structures. Thin filament reconstructions were generated from the EM data using these starting models as references. In addition to showing the core domain of troponin, the reconstructions showed additional detail not present in the starting models. We attribute this to an extension of TnI linking the troponin core domain to actin at low (but not at high) Ca2+, thereby trapping tropomyosin in the OFF-state. The bulk of the core domain of troponin appears not to move significantly on actin, regardless of Ca2+ level. Our observations suggest a simple model for muscle regulation in which troponin affects the charge balance on actin and hence tropomyosin position.</p>
dc.identifier.submissionpathcraig/14
dc.contributor.departmentDepartment of Cell Biology
dc.source.pages707-17


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