Activation of Myocardial Contraction by the N-Terminal Domains of Myosin Binding Protein-C

Herron, Todd J.; Rostkova, Elena; Kunst, Gudrun; Chaturvedi, Rajiv; Gautel, Mathias; Kentish, Jonathan C.

doi:10.1161/01.res.0000222059.54917.ef

Cited by 83 publications

(118 citation statements)

References 37 publications

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“…This mechanism could explain observations that C0C2 activates thin-filament motility in vitro (14). It could also explain force development in sarcomeres in low Ca 2ϩ (31) and the apparent increased Ca 2ϩ sensitivity of cross-bridge cycling (5,32). The predicted overlap of binding sites for C0 and C1 and tropomyosin under low-Ca 2ϩ conditions suggests that cMyBP-C may interact more strongly with the thin filament at high Ca 2ϩ (33) or in the presence of strongly bound cross-bridges, i.e., when the thin filament is fully activated and cross-bridge-binding sites are completely uncovered.…”

Section: Discussionmentioning

confidence: 82%

Cardiac myosin-binding protein C decorates F-actin: Implications for cardiac function

Whitten

Jeffries

Harris

et al. 2008

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

115

138

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Cardiac myosin-binding protein C (cMyBP-C) is an accessory protein of striated muscle sarcomeres that is vital for maintaining regular heart function. Its 4 N-terminal regulatory domains, C0-C1-m-C2 (C0C2), influence actin and myosin interactions, the basic contractile proteins of muscle. Using neutron contrast variation data, we have determined that C0C2 forms a repeating assembly with filamentous actin, where the C0 and C1 domains of C0C2 attach near the DNase I-binding loop and subdomain 1 of adjacent actin monomers. Direct interactions between the N terminus of cMyBP-C and actin thereby provide a mechanism to modulate the contractile cycle by affecting the regulatory state of the thin filament and its ability to interact with myosin.familial hypertrophic cardiomypathy ͉ C protein ͉ muscle regulation ͉ neutron contrast variation ͉ small-angle scattering I nterest in cardiac myosin-binding protein C (cMyBP-C) has been stimulated in recent times because of its influence on fine-tuning heart muscle contraction and its links to inherited cardiac disorders (1). Medical research estimates that up to 1 in 500 adolescents and young adults is affected by the diverse genetic condition known as familial hypertrophic cardiomyopathy (FHC) (2), which presents as a gradual thickening of the ventricle walls of the heart and a correlated increase in the risk of heart failure. Approximately 63% of FHC cases are attributable to mutations in genes that encode sarcomeric proteins, the majority of which (42%) are mutations in the MYBPC3 gene (3). Of the 150 known FHC-causing mutations distributed throughout the MYBPC3 gene, 26 are located in the region that encodes the 4 N-terminal domains of the protein.The primary components of muscle thick and thin filaments are the proteins myosin and actin, respectively. Muscle shortens and develops force as thin filaments slide past thick filaments via the cyclic interactions of myosin cross-bridges (myosin-S1) extending from the thick filament to actin. These actomyosin interactions are regulated in part by calcium signals that are transmitted via thin-filament accessory proteins troponin and tropomyosin, whose movement on the thin filament unveils myosin-binding sites, permitting productive (weak to strong binding) cross-bridge transitions (4). Originally identified as a thick filament accessory protein, myosin-binding protein C (MyBP-C) also provides a thick-filament accessory protein, provides an additional regulatory layer to the contractile cycle, but the precise molecular mechanisms by which it influences actomyosin interactions are not understood. Belonging to the Ig/fibronectin superfamily of proteins, cMyBP-C consists of 11 sequentially ordered domains (C1, m, C2-C10, common to all isoforms), plus a cardiac specific N-terminal domain (C0) and proline/alanine-rich region that links C0 to C1. The N-terminal domains (C0-C1-m-C2 or C0C2) perform the regulatory functions by influencing myosin head interactions with actin filaments (5-7), whereas the C-terminal domains of cMyBP-C (C7-C10...

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Section: Discussionmentioning

confidence: 82%

Cardiac myosin-binding protein C decorates F-actin: Implications for cardiac function

Whitten

Jeffries

Harris

et al. 2008

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

115

138

View full text Add to dashboard Cite

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“…This could increase the freedom of movement of Tm so that single S1 binding events are no longer significantly inhibited. Physiological experiments in which N-terminal fragments of cMyBP-C are diffused into skinned myocytes (46,47) also demonstrate activation of contraction at low (relaxing) Ca 2+ concentrations. In these experiments, it was suggested that cMyBP-C affects crossbridge cycling primarily by binding to myosin, thus affecting myosin crossbridge mechanics, although mechanisms involving actin binding were also considered possible.…”

Section: Discussionmentioning

confidence: 93%

“…Previous modeling suggested that the C0 and C1 domains could clash with Tm in its blocked position (25,27,28), whereas experiments in which expressed N-terminal fragments were added to skinned cardiac myocytes implicated the ProAla-rich domain between C0 and C1 in modulating Ca 2+ activation of crossbridge cycling (46). However, in similar skinned fiber experiments, the ProAla-rich domain was found to have no effect, whereas the C1 and M-domains were critical to the Ca 2+ -sensitizing and activating effects of various N-terminal domains (48).…”

Section: Discussionmentioning

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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“…Fiber studies using N-terminal domain fragments at high stoichiometric concentrations demonstrate that the addition of the C1-C2 or C0-C2 peptide results in a leftward shift in the pCa-tension curve with or without the presence of native cMyBP-C [18][19][20]. When the C0 domain of MyBP-C was deleted in a transgenic model, again a leftward shift in fiber pCatension relation was observed [8].…”

Section: Introductionmentioning

confidence: 98%

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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Activation of Myocardial Contraction by the N-Terminal Domains of Myosin Binding Protein-C

Cited by 83 publications

References 37 publications

Cardiac myosin-binding protein C decorates F-actin: Implications for cardiac function

Cardiac myosin-binding protein C decorates F-actin: Implications for cardiac function

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

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

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