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AuthorStanczyk P.J.
AuthorSeidel M.
AuthorWhite J.
AuthorViero C.
AuthorGeorge C.H.
AuthorZissimopoulos S.
AuthorLai F.A.
Available date2020-03-18T08:10:09Z
Publication Date2018
Publication NameJournal of Cell Science
ResourceScopus
ISSN219533
URIhttp://dx.doi.org/10.1242/jcs.210443
URIhttp://hdl.handle.net/10576/13332
AbstractThe cardiac muscle ryanodine receptor-Ca2+ release channel (RyR2) constitutes the sarcoplasmic reticulum (SR) Ca2+ efflux mechanism that initiates myocyte contraction, while cardiac myosin-binding protein-C (cMyBP-C; also known as MYBPC3) mediates regulation of acto-myosin cross-bridge cycling. In this paper, we provide the first evidence for the presence of direct interaction between these two proteins, forming a RyR2-cMyBP-C complex. The C-terminus of cMyBP-C binds with the RyR2 N-terminus in mammalian cells and the interaction is not mediated by a fibronectin-like domain. Notably, we detected complex formation between both recombinant cMyBP-C and RyR2, as well as between the native proteins in cardiac tissue. Cellular Ca2+ dynamics in HEK293 cells is altered upon co-expression of cMyBP-C and RyR2, with lowered frequency of RyR2-mediated spontaneous Ca2+ oscillations, suggesting that cMyBP-C exerts a potential inhibitory effect on RyR2-dependent Ca2+ release. Discovery of a functional RyR2 association with cMyBP-C provides direct evidence for a putative mechanistic link between cytosolic soluble cMyBP-C and SR-mediated Ca2+ release, via RyR2. Importantly, this interaction may have clinical relevance to the observed cMyBP-C and RyR2 dysfunction in cardiac pathologies, such as hypertrophic cardiomyopathy. ? 2018. Published by The Company of Biologists Ltd.
SponsorThis work was supported by a British Heart Foundation Fellowship to S.Z. (FS/15/30/ 31494). Deposited in PMC for immediate release.
Languageen
PublisherCompany of Biologists Ltd
SubjectCa2+ signalling
Excitation-contraction coupling
Myosin-binding protein C
Ryanodine receptor
Sarcomere
Sarcoplasmic reticulum
TitleAssociation of cardiac myosin-binding protein-C with the ryanodine receptor channel - putative retrograde regulation?
TypeArticle
Pagination9
Issue Number15
Volume Number131


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