A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy.

Yang, Qinglin; Sanbe, Atsushi; Osińska, Hanna; Hewett, Timothy E.; Klevitsky, Raisa; Robbins, Jeffrey

doi:10.1172/jci3880

Cited by 181 publications

(137 citation statements)

References 37 publications

(43 reference statements)

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“…A line was selected whose expression levels matched the previously generated cMyBP-C WT mice. Approximately 35% replacement with cMyBP-C AllPϩ occurred in line 34, which is equivalent to the level of replacement previously measured in the cMyBP-C WT -expressing hearts [line 21 (16)] that expressed myc-tagged WT cMyBP-C (Fig. 6, which is published as supporting information on the PNAS web site).…”

supporting

confidence: 68%

Cardiac myosin binding protein c phosphorylation is cardioprotective

Sadayappan

Osińska

Klevitsky

et al. 2006

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

191

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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supporting

confidence: 68%

Cardiac myosin binding protein c phosphorylation is cardioprotective

Sadayappan

Osińska

Klevitsky

et al. 2006

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

191

294

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“…For example, myosin-binding protein C (MyBP-C) is a component of the thick filament and is distributed every 43 nm within the C-zone of the sarcomere, where the cross-bridges are found (Offer et al, 1972). Transgenic mice expressing truncated MyBP-C that lacks the myosin-binding site in cardiac muscle exhibit significant sarcomere disorganization (Yang et al, 1998 nerve in the two groups of mice. 10 d later the animals were killed, and extracts of the gastrocnemius muscles were prepared.…”

Section: Murf1 Binds a Specific Subset Of Muscle Proteinsmentioning

confidence: 99%

During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation

Cohen¹,

Brault²,

Gygi³

et al. 2009

J Exp Med

124

186

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“…Furthermore, while sedimentation studies indicate that cMyBP-C does not bind to myosin subfragment 1 (S1) [3], the C0-C1 domains may interact with the myosin head and affect contractile function [7,8]. The importance of cMyBP-C in fiber assembly, maintenance of structural integrity, and regulation of contraction is highlighted by the fact that mutations in cMyBP-C are one of the most commonly identified causes of familial hypertrophic cardiomyopathy [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Cardiac myosin binding protein-C modulates actomyosin binding and kinetics in the in vitro motility assay

Saber

Begin

Warshaw

et al. 2008

Journal of Molecular and Cellular Cardiology

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The modulatory role of whole cardiac myosin binding protein-C (cMyBP-C) on myosin force and motion generation was assessed in an in vitro motility assay. The presence of cMyBP-C at an approximate molar ratio of cMyBP-C to whole myosin of 1:2, resulted in a 25% reduction in thin filament velocity (P<0.002) with no effect on relative isometric force under maximally activated conditions (pCa 5). Cardiac MyBP-C was capable of inhibiting actin filament velocity in a concentration-dependent manner using either whole myosin, HMM or S1, indicating that the cMyBP-C does not have to bind to myosin LMM or S2 subdomains to exert its effect. The reduction in velocity by cMyBP-C was independent of changes in ionic strength or excess inorganic phosphate. Cosedimentation experiments demonstrated S1 binding to actin is reduced as a function of cMyBP-C concentration in the presence of ATP. In contrast, S1 avidly bound to actin in the absence of ATP and limited cMyBP-C binding, indicating that cMyBP-C and S1 compete for actin binding in an ATP-dependent fashion. However, based on the relationship between thin filament velocity and filament length, the cMyBP-C induced reduction in velocity was independent of the number of crossbridges interacting with the thin filament. In conclusion, the effects of cMyBP-C on velocity and force at both maximal and submaximal activation demonstrate that cMyBP-C does not solely act as a tether between the myosin S2 and LMM subdomains but likely affects both the kinetics and recruitment of myosin cross-bridges through its direct interaction with actin and/or myosin head.

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A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy.

Cited by 181 publications

References 37 publications

Cardiac myosin binding protein c phosphorylation is cardioprotective

Cardiac myosin binding protein c phosphorylation is cardioprotective

During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation

Cardiac myosin binding protein-C modulates actomyosin binding and kinetics in the in vitro motility assay

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