Structural Evidence for the Interaction of C-protein (MyBP-C) with Actin and Sequence Identification of a Possible Actin-binding Domain

Squire, John M.; Luther, Pradeep K.; Knupp, Carlo

doi:10.1016/s0022-2836(03)00781-2

Cited by 148 publications

(180 citation statements)

References 59 publications

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“…Presently, with the use of monodispersed myosin at a 2:1 whole myosin/cMyBP-C molar ratio, we have demonstrated that cMyBP-C directly affects actomyosin kinetics with the effect being independent of cMyBP-C binding to the LMM and S2 domains of myosin. These results raise the possibility that cMyBP-C exerts its modulatory role via its interaction with actin, which may be a regulated property depending on cMyBP-C's phosphorylation state [6]. It should be noted that neither the specific cMyBP-C binding site on actin nor the physiologic relevance of such binding in muscle fibers (if present) has been defined.…”

Section: Discussionmentioning

confidence: 87%

“…Moreover, in the force experiments a similar concentration of α-actinin was used to arrest thin filament motility at high calcium concentrations which would not be anticipated if cMyBP-C was imposing a load on the system. Alternatively, it has been proposed that cMyBP-C may bind directly to actin [6] and through this interaction affect contractile function. Since myosin S1 does not bind cMyBP-C [3], the inhibition of actin velocities observed using myosin S1 would suggest that this effect is mediated via cMyBP-C binding to actin.…”

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: 87%

Section: Discussionmentioning

confidence: 99%

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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“…An increasing number of results indicate that the N-terminal domains of cMyBP-C influence force activation through a direct interaction with actin. 71,[73][74][75] Data from small-angle solution scattering have provided new insights into the structure of cMyBP-C and its interactions with actin and how they might modulate the primary Ca 21 -signal.…”

Section: Cardiac Myosin Binding Protein Cmentioning

confidence: 99%

Invited review: Probing the structures of muscle regulatory proteins using small‐angle solution scattering

Jeffries

Trewhella

2011

Biopolymers

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Small‐angle X‐ray and neutron scattering with contrast variation have made important contributions in advancing our understanding of muscle regulatory protein structures in the context of the dynamic molecular processes governing muscle action. The contributions of the scattering investigations have depended upon the results of key crystallographic, NMR, and electron microscopy experiments that have provided detailed structural information that has aided in the interpretation of the scattering data. This review will cover the advances made using small‐angle scattering techniques, in combination with the results from these complementary techniques, in probing the structures of troponin and myosin binding protein C. A focus of the troponin work has been to understand the isoform differences between the skeletal and cardiac isoforms of this major calcium receptor in muscle. In the case of myosin binding protein C, significant data are accumulating, indicating that this protein may act to modulate the primary calcium signals from troponin, and interest in its biological role has grown because of linkages between gene mutations in the cardiac isoform and serious heart disease. © 2011 Wiley Periodicals, Inc. Biopolymers 95: 505–516, 2011.

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“…Based on X-ray diffraction data from intact skeletal muscle, it has been proposed that the N terminus of MyBP-C interacts with actin (15,16). However, the functional significance of these interactions to muscle contraction is not known, and direct structural evidence of MyBP-C/actin binding has been lacking.…”

mentioning

confidence: 99%

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.

114

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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Structural Evidence for the Interaction of C-protein (MyBP-C) with Actin and Sequence Identification of a Possible Actin-binding Domain

Cited by 148 publications

References 59 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

Invited review: Probing the structures of muscle regulatory proteins using small‐angle solution scattering

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

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