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dc.contributor.authorKensler, Robert W.
dc.contributor.authorCraig, Roger
dc.contributor.authorMoss, Richard L.
dc.date2022-08-11T08:09:47.000
dc.date.accessioned2022-08-23T16:43:26Z
dc.date.available2022-08-23T16:43:26Z
dc.date.issued2017-02-21
dc.date.submitted2017-06-21
dc.identifier.citationProc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1355-E1364. doi: 10.1073/pnas.1614020114. Epub 2017 Feb 6. <a href="https://doi.org/10.1073/pnas.1614020114">Link to article on publisher's site</a>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.1614020114
dc.identifier.pmid28167762
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40295
dc.description.abstractCardiac myosin binding protein C (cMyBP-C) has a key regulatory role in cardiac contraction, but the mechanism by which changes in phosphorylation of cMyBP-C accelerate cross-bridge kinetics remains unknown. In this study, we isolated thick filaments from the hearts of mice in which the three serine residues (Ser273, Ser282, and Ser302) that are phosphorylated by protein kinase A in the m-domain of cMyBP-C were replaced by either alanine or aspartic acid, mimicking the fully nonphosphorylated and the fully phosphorylated state of cMyBP-C, respectively. We found that thick filaments from the cMyBP-C phospho-deficient hearts had highly ordered cross-bridge arrays, whereas the filaments from the cMyBP-C phospho-mimetic hearts showed a strong tendency toward disorder. Our results support the hypothesis that dephosphorylation of cMyBP-C promotes or stabilizes the relaxed/superrelaxed quasi-helical ordering of the myosin heads on the filament surface, whereas phosphorylation weakens this stabilization and binding of the heads to the backbone. Such structural changes would modulate the probability of myosin binding to actin and could help explain the acceleration of cross-bridge interactions with actin when cMyBP-C is phosphorylated because of, for example, activation of beta1-adrenergic receptors in myocardium.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=28167762&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsFreely available online through the PNAS open access option.
dc.subjectcMyBP-C
dc.subjectcardiac myosin binding protein C
dc.subjectcardiac myosin binding protein C function
dc.subjectcardiac thick filament
dc.subjectcardiac thick filament structure
dc.subjectBiochemistry
dc.subjectCell Biology
dc.subjectCellular and Molecular Physiology
dc.titlePhosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume114
dc.source.issue8
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4102&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/3097
dc.identifier.contextkey10331029
refterms.dateFOA2022-08-23T16:43:26Z
html.description.abstract<p>Cardiac myosin binding protein C (cMyBP-C) has a key regulatory role in cardiac contraction, but the mechanism by which changes in phosphorylation of cMyBP-C accelerate cross-bridge kinetics remains unknown. In this study, we isolated thick filaments from the hearts of mice in which the three serine residues (Ser273, Ser282, and Ser302) that are phosphorylated by protein kinase A in the m-domain of cMyBP-C were replaced by either alanine or aspartic acid, mimicking the fully nonphosphorylated and the fully phosphorylated state of cMyBP-C, respectively. We found that thick filaments from the cMyBP-C phospho-deficient hearts had highly ordered cross-bridge arrays, whereas the filaments from the cMyBP-C phospho-mimetic hearts showed a strong tendency toward disorder. Our results support the hypothesis that dephosphorylation of cMyBP-C promotes or stabilizes the relaxed/superrelaxed quasi-helical ordering of the myosin heads on the filament surface, whereas phosphorylation weakens this stabilization and binding of the heads to the backbone. Such structural changes would modulate the probability of myosin binding to actin and could help explain the acceleration of cross-bridge interactions with actin when cMyBP-C is phosphorylated because of, for example, activation of beta1-adrenergic receptors in myocardium.</p>
dc.identifier.submissionpathoapubs/3097
dc.contributor.departmentCraig Lab
dc.contributor.departmentDepartment of Radiology
dc.contributor.departmentDepartment of Cell and Developmental Biology
dc.source.pagesE1355-E1364


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