Myosin binding protein C: Structural abnormalities in familial hypertrophic cardiomyopathy

Oakley, Cecily E.; Hambly, Brett D.; Curmi, Paul M. G.; Brown, Louise J.

doi:10.1038/sj.cr.7290208

Cited by 54 publications

(52 citation statements)

References 90 publications

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“…1A). The domain assignments were performed based on the alignment of MyBPC isoforms from different species (24). Protein C0 -C1 included the proline-alanine-rich domain that was suggested to interact with actin based on a structural modeling (11).…”

Section: Resultsmentioning

confidence: 99%

Myosin Binding Protein C Interaction with Actin

Rybakova

Greaser

Moss

2011

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Myosin Binding Protein C Interaction with Actin

Rybakova

Greaser

Moss

2011

Journal of Biological Chemistry

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“…The location of the flexible phosphorylation motif at the cMyBP-C N terminus appears to be critical in permitting shuttling between the thick and thin filaments (20). Phosphorylation also can modulate the myosin-actin interactions that are necessary to maintain thick filament organization (15).…”

Section: Discussionmentioning

confidence: 99%

Cardiac myosin binding protein c phosphorylation is cardioprotective

Sadayappan

Osińska

Klevitsky

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

190

294

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Cardiac myosin binding protein C (cMyBP-C) has three phosphorylatable serines at its N terminus (Ser-273, Ser-282, and Ser-302), and the residues' phosphorylation states may alter thick filament structure and function. To examine the effects of cMyBP-C phosphorylation, we generated transgenic mice with cardiac-specific expression of a cMyBP-C in which the three phosphorylation sites were mutated to aspartic acid, mimicking constitutive phosphorylation (cMyBP-C AllP؉ ). The allele was bred into a cMyBP-C null background (cMyBP-C (t/t) ) to ensure the absence of endogenous dephosphorylated cMyBP-C. cMyBP-C AllP؉ was incorporated normally into the cardiac sarcomere and restored normal cardiac function in the null background. However, subtle changes in sarcomere ultrastructure, characterized by increased distances between the thick filaments, indicated that phosphomimetic cMyBP-C affects thick-thin filament relationships, and yeast two-hybrid data and pull-down studies both showed that charged residues in these positions effectively prevented interaction with the myosin heavy chain. Confirming the physiological relevance of these data, the cMyBP-C AllP؉:(t/t) hearts were resistant to ischemia-reperfusion injury. These data demonstrate that cMyBP-C phosphorylation functions in maintaining thick filament spacing and structure and can help protect the myocardium from ischemic injury.heart ͉ ischemia C ardiac myosin binding protein C (cMyBP-C) is localized to the sarcomere's thick filaments where it has structural and regulatory functions. MYBPC3 mutations account for 20-30% of all mutations linked to familial hypertrophic cardiomyopathy (1). cMyBP-C belongs to the intracellular Ig superfamily and is composed of Ig and fibronectin type-3 repeating domains (Fig. 1A). It is present not only in cardiac muscle, but also in skeletal muscle before the skeletal muscle-type isoforms are expressed, suggesting that the cardiac isoform is functional in early myofibrillogenesis and regenerating muscle (2, 3). cMyBP-C may modulate myosin assembly (4) and stabilize thick filaments (5). It binds titin via domains C8-C10 (6) and actin in the Pro-Alarich sequences between the C0 and C1 domains (7), which appear to be important for the precise arrangement of the actin-myosin filaments. Compared with the two skeletal muscle isoforms, the cardiac isoform contains an extra Ig domain at the N terminus (C0), an insertion of 28 residues within the C5 domain, and three potential phosphorylation sites that are substrates for cAMP-dependent PKA, Ca 2ϩ -calmodulin-activated kinase, and PKC (8). This region is located between the C1 and C2 domains of the N terminus, which binds to the subfragment 2 (S2) segment of myosin close to the lever arm domain (9-11), and this interaction may be dynamically regulated by the differential phosphorylation of cMyBP-C (12). cMyBP-C is the only thick filament protein that is differentially phosphorylated at multiple sites by the enzymes PKA, PKC, and Ca 2ϩ -calmodulin-activated kinase (13). Reconstitution studie...

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“…We therefore et al (1992). The skeletal MyBPC isoforms lack the N-terminal C0 domain, two of the three phosphorylation sites, and a proline-rich insert in the C5 domain (Oakley et al, 2004), compared with the cardiac isoform. Skeletal MyBPC has been shown to bind in the sarcomere in a similar manner as the cardiac isoform (Freiburg and Gautel, 1996;Gilbert et al, 1999;Luther et al, 2008), and MyBPC-1 has been shown to undergo phosphorylation (Ackermann and KontrogianniKonstantopoulos, 2011).…”

Section: Mechanical Analysismentioning

confidence: 99%