The binding of skeletal muscle C-protein to F-actin, and its relation to the interaction of actin with myosin subfragment-1

Moos, Carl; Mason, Craig M.; Besterman, Jeffrey M.; Feng, I-Nan M.; Dubin, Jeffrey H.

doi:10.1016/0022-2836(78)90172-9

Cited by 176 publications

(178 citation statements)

References 30 publications

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“…A determinant of isometric force is the duty ratio, defined as the myosin attachment time divided by the total cycle time (i.e., time of the ATP hydrolysis cycle). As maximal isometric force is unaffected by cMyBP-C, this would suggest that the ATP hydrolysis rate is likely slowed [5] accordingly so that the duty ratio is preserved in the presence of cMyBP-C. Why this is not the case at submaximal calcium levels where force is reduced in the presence of cMyBP-C is a matter of speculation. As crossbridge kinetics are differentially affected by load and the degree of calcium activation [50], these data would suggest that cross-bridge number and kinetics are likely responsible for the differential effect of cMyBP-C on both force and velocity at submaximal calcium.…”

Section: Discussionmentioning

confidence: 99%

“…The protein consists of 11 domains (C0-C10), 8 immunoglobulin I-like and 3 fibronectin type 3 motifs, with putative binding of specific domains to the myosin tail (domain C10) [1], titin (domains C8-C10) [2], myosin sub-fragment 2 (S2, domains C1-C2) [3,4], and actin (domains C0-C1) [5,6]. 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].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…In addition to binding to myosin, MyBP-C also interacts with actin (12) and with thin filaments (13) via its N-terminal region (9, 10, 14-17; cf. 18).…”

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confidence: 99%

Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism

Mun

Previs

et al. 2014

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

148

207

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Significance Myosin-binding protein C (MyBP-C) is a component of myosin filaments, one of the two sets of contractile elements whose relative sliding is the basis of muscle contraction. In the heart, MyBP-C modulates contractility in response to cardiac stimulation; mutations in MyBP-C lead to cardiac disease. The mechanism by which MyBP-C modulates cardiac contraction is not understood. Using electron microscopy and a light microscopic assay for filament sliding, we demonstrate that MyBP-C binds to the other set of filaments, containing actin and the regulatory component, tropomyosin. In so doing, it displaces tropomyosin from its inhibitory position to activate actin filament interaction with myosin, promoting filament sliding. These findings provide insights into the molecular basis of heart function.

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“…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.…”

mentioning

confidence: 99%

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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The binding of skeletal muscle C-protein to F-actin, and its relation to the interaction of actin with myosin subfragment-1

Cited by 176 publications

References 30 publications

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

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

Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism

Cardiac myosin binding protein c phosphorylation is cardioprotective

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