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dc.contributor.authorMun, Ji Young
dc.contributor.authorKensler, Robert W.
dc.contributor.authorHarris, Samantha P.
dc.contributor.authorCraig, Roger
dc.date2022-08-11T08:08:03.000
dc.date.accessioned2022-08-23T15:40:53Z
dc.date.available2022-08-23T15:40:53Z
dc.date.issued2016-02-01
dc.date.submitted2016-05-31
dc.identifier.citationJ Mol Cell Cardiol. 2016 Feb;91:141-7. doi: 10.1016/j.yjmcc.2015.12.014. Epub 2015 Dec 21. <a href="http://dx.doi.org/10.1016/j.yjmcc.2015.12.014">Link to article on publisher's site</a>
dc.identifier.issn0022-2828 (Linking)
dc.identifier.doi10.1016/j.yjmcc.2015.12.014
dc.identifier.pmid26718724
dc.identifier.urihttp://hdl.handle.net/20.500.14038/26500
dc.description.abstractMutations in cardiac myosin binding protein C (cMyBP-C), a thick filament protein that modulates contraction of the heart, are a leading cause of hypertrophic cardiomyopathy (HCM). Electron microscopy and 3D reconstruction of thin filaments decorated with cMyBP-C N-terminal fragments suggest that one mechanism of this modulation involves the interaction of cMyBP-C's N-terminal domains with thin filaments to enhance their Ca(2+)-sensitivity by displacement of tropomyosin from its blocked (low Ca(2+)) to its closed (high Ca(2+)) position. The extent of this tropomyosin shift is reduced when cMyBP-C N-terminal domains are phosphorylated. In the current study, we have examined L348P, a sequence variant of cMyBP-C first identified in a screen of patients with HCM. In L348P, leucine 348 is replaced by proline in cMyBP-C's regulatory M-domain, resulting in an increase in cMyBP-C's ability to enhance thin filament Ca(2+)-sensitization. Our goal here was to determine the structural basis for this enhancement by carrying out 3D reconstruction of thin filaments decorated with L348P-mutant cMyBP-C. When thin filaments were decorated with wild type N-terminal domains at low Ca(2+), tropomyosin moved from the blocked to the closed position, as found previously. In contrast, the L348P mutant caused a significantly larger tropomyosin shift, to approximately the open position, consistent with its enhancement of Ca(2+)-sensitization. Phosphorylated wild type fragments showed a smaller shift than unphosphorylated fragments, whereas the shift induced by the L348P mutant was not affected by phosphorylation. We conclude that the L348P mutation causes a gain of function by enhancing tropomyosin displacement on the thin filament in a phosphorylation-independent way.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26718724&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1016/j.yjmcc.2015.12.014
dc.subjectCardiac muscle
dc.subjectElectron microscopy
dc.subjectHypertrophic cardiomyopathy
dc.subjectMyosin binding protein C
dc.subjectThin filament
dc.subjectcMyBP-C
dc.subjectBiophysics
dc.subjectCell Biology
dc.titleThe cMyBP-C HCM variant L348P enhances thin filament activation through an increased shift in tropomyosin position
dc.typeJournal Article
dc.source.journaltitleJournal of molecular and cellular cardiology
dc.source.volume91
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/cellbiology_pp/187
dc.identifier.contextkey8667045
html.description.abstract<p>Mutations in cardiac myosin binding protein C (cMyBP-C), a thick filament protein that modulates contraction of the heart, are a leading cause of hypertrophic cardiomyopathy (HCM). Electron microscopy and 3D reconstruction of thin filaments decorated with cMyBP-C N-terminal fragments suggest that one mechanism of this modulation involves the interaction of cMyBP-C's N-terminal domains with thin filaments to enhance their Ca(2+)-sensitivity by displacement of tropomyosin from its blocked (low Ca(2+)) to its closed (high Ca(2+)) position. The extent of this tropomyosin shift is reduced when cMyBP-C N-terminal domains are phosphorylated. In the current study, we have examined L348P, a sequence variant of cMyBP-C first identified in a screen of patients with HCM. In L348P, leucine 348 is replaced by proline in cMyBP-C's regulatory M-domain, resulting in an increase in cMyBP-C's ability to enhance thin filament Ca(2+)-sensitization. Our goal here was to determine the structural basis for this enhancement by carrying out 3D reconstruction of thin filaments decorated with L348P-mutant cMyBP-C. When thin filaments were decorated with wild type N-terminal domains at low Ca(2+), tropomyosin moved from the blocked to the closed position, as found previously. In contrast, the L348P mutant caused a significantly larger tropomyosin shift, to approximately the open position, consistent with its enhancement of Ca(2+)-sensitization. Phosphorylated wild type fragments showed a smaller shift than unphosphorylated fragments, whereas the shift induced by the L348P mutant was not affected by phosphorylation. We conclude that the L348P mutation causes a gain of function by enhancing tropomyosin displacement on the thin filament in a phosphorylation-independent way.</p>
dc.identifier.submissionpathcellbiology_pp/187
dc.contributor.departmentDepartment of Cell and Developmental Biology
dc.source.pages141-7


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