The cMyBP-C HCM variant L348P enhances thin filament activation through an increased shift in tropomyosin position
dc.contributor.author | Mun, Ji Young | |
dc.contributor.author | Kensler, Robert W. | |
dc.contributor.author | Harris, Samantha P. | |
dc.contributor.author | Craig, Roger | |
dc.date | 2022-08-11T08:08:03.000 | |
dc.date.accessioned | 2022-08-23T15:40:53Z | |
dc.date.available | 2022-08-23T15:40:53Z | |
dc.date.issued | 2016-02-01 | |
dc.date.submitted | 2016-05-31 | |
dc.identifier.citation | J 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.issn | 0022-2828 (Linking) | |
dc.identifier.doi | 10.1016/j.yjmcc.2015.12.014 | |
dc.identifier.pmid | 26718724 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/26500 | |
dc.description.abstract | 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. | |
dc.language.iso | en_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.url | http://dx.doi.org/10.1016/j.yjmcc.2015.12.014 | |
dc.subject | Cardiac muscle | |
dc.subject | Electron microscopy | |
dc.subject | Hypertrophic cardiomyopathy | |
dc.subject | Myosin binding protein C | |
dc.subject | Thin filament | |
dc.subject | cMyBP-C | |
dc.subject | Biophysics | |
dc.subject | Cell Biology | |
dc.title | The cMyBP-C HCM variant L348P enhances thin filament activation through an increased shift in tropomyosin position | |
dc.type | Journal Article | |
dc.source.journaltitle | Journal of molecular and cellular cardiology | |
dc.source.volume | 91 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/cellbiology_pp/187 | |
dc.identifier.contextkey | 8667045 | |
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.submissionpath | cellbiology_pp/187 | |
dc.contributor.department | Department of Cell and Developmental Biology | |
dc.source.pages | 141-7 |