Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism
dc.contributor.author | Mun, Ji Young | |
dc.contributor.author | Previs, Michael J. | |
dc.contributor.author | Yu, Hope Y. | |
dc.contributor.author | Gulick, James | |
dc.contributor.author | Tobacman, Larry S. | |
dc.contributor.author | Beck Previs, Samantha | |
dc.contributor.author | Robbins, Jeffrey | |
dc.contributor.author | Warshaw, David M. | |
dc.contributor.author | Craig, Roger | |
dc.date | 2022-08-11T08:08:12.000 | |
dc.date.accessioned | 2022-08-23T15:46:04Z | |
dc.date.available | 2022-08-23T15:46:04Z | |
dc.date.issued | 2014-02-11 | |
dc.date.submitted | 2014-06-10 | |
dc.identifier.citation | Mun JY, Previs MJ, Yu HY, Gulick J, Tobacman LS, Beck Previs S, Robbins J, Warshaw DM, Craig R. Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism. Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2170-5. doi: 10.1073/pnas.1316001111. <a href="http://dx.doi.org/10.1073/pnas.1316001111">Link to article on publisher's site</a> | |
dc.identifier.issn | 0027-8424 (Linking) | |
dc.identifier.doi | 10.1073/pnas.1316001111 | |
dc.identifier.pmid | 24477690 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/27674 | |
dc.description.abstract | Myosin-binding protein C (MyBP-C) is an accessory protein of striated muscle thick filaments and a modulator of cardiac muscle contraction. Defects in the cardiac isoform, cMyBP-C, cause heart disease. cMyBP-C includes 11 Ig- and fibronectin-like domains and a cMyBP-C-specific motif. In vitro studies show that in addition to binding to the thick filament via its C-terminal region, cMyBP-C can also interact with actin via its N-terminal domains, modulating thin filament motility. Structural observations of F-actin decorated with N-terminal fragments of cMyBP-C suggest that cMyBP-C binds to actin close to the low Ca(2+) binding site of tropomyosin. This suggests that cMyBP-C might modulate thin filament activity by interfering with tropomyosin regulatory movements on actin. To determine directly whether cMyBP-C binding affects tropomyosin position, we have used electron microscopy and in vitro motility assays to study the structural and functional effects of N-terminal fragments binding to thin filaments. 3D reconstructions suggest that under low Ca(2+) conditions, cMyBP-C displaces tropomyosin toward its high Ca(2+) position, and that this movement corresponds to thin filament activation in the motility assay. At high Ca(2+), cMyBP-C had little effect on tropomyosin position and caused slowing of thin filament sliding. Unexpectedly, a shorter N-terminal fragment did not displace tropomyosin or activate the thin filament at low Ca(2+) but slowed thin filament sliding as much as the larger fragments. These results suggest that cMyBP-C may both modulate thin filament activity, by physically displacing tropomyosin from its low Ca(2+) position on actin, and govern contractile speed by an independent molecular mechanism. | |
dc.language.iso | en_US | |
dc.relation | <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=24477690&dopt=Abstract">Link to Article in PubMed</a> | |
dc.rights | <p>Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.</p> | |
dc.subject | Animals | |
dc.subject | Calcium | |
dc.subject | Carrier Proteins | |
dc.subject | Chickens | |
dc.subject | Microscopy, Electron | |
dc.subject | Myocardium | |
dc.subject | Tropomyosin | |
dc.subject | Biophysics | |
dc.subject | Cell Biology | |
dc.subject | Cellular and Molecular Physiology | |
dc.title | Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism | |
dc.type | Journal Article | |
dc.source.journaltitle | Proceedings of the National Academy of Sciences of the United States of America | |
dc.source.volume | 111 | |
dc.source.issue | 6 | |
dc.identifier.legacyfulltext | https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1025&context=craig&unstamped=1 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/craig/26 | |
dc.identifier.contextkey | 5676450 | |
refterms.dateFOA | 2022-08-23T15:46:04Z | |
html.description.abstract | <p>Myosin-binding protein C (MyBP-C) is an accessory protein of striated muscle thick filaments and a modulator of cardiac muscle contraction. Defects in the cardiac isoform, cMyBP-C, cause heart disease. cMyBP-C includes 11 Ig- and fibronectin-like domains and a cMyBP-C-specific motif. In vitro studies show that in addition to binding to the thick filament via its C-terminal region, cMyBP-C can also interact with actin via its N-terminal domains, modulating thin filament motility. Structural observations of F-actin decorated with N-terminal fragments of cMyBP-C suggest that cMyBP-C binds to actin close to the low Ca(2+) binding site of tropomyosin. This suggests that cMyBP-C might modulate thin filament activity by interfering with tropomyosin regulatory movements on actin. To determine directly whether cMyBP-C binding affects tropomyosin position, we have used electron microscopy and in vitro motility assays to study the structural and functional effects of N-terminal fragments binding to thin filaments. 3D reconstructions suggest that under low Ca(2+) conditions, cMyBP-C displaces tropomyosin toward its high Ca(2+) position, and that this movement corresponds to thin filament activation in the motility assay. At high Ca(2+), cMyBP-C had little effect on tropomyosin position and caused slowing of thin filament sliding. Unexpectedly, a shorter N-terminal fragment did not displace tropomyosin or activate the thin filament at low Ca(2+) but slowed thin filament sliding as much as the larger fragments. These results suggest that cMyBP-C may both modulate thin filament activity, by physically displacing tropomyosin from its low Ca(2+) position on actin, and govern contractile speed by an independent molecular mechanism.</p> | |
dc.identifier.submissionpath | craig/26 | |
dc.contributor.department | Department of Cell and Developmental Biology | |
dc.source.pages | 2170-5 |
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