doi: 10.1161/01.RES.0000127175.21818.C2
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© 2004 American Heart Association, Inc.
Reviews |
Cardiac Myosin Binding Protein C
Its Role in Physiology and Disease
From the Department of Cardiovascular Medicine (E.F., C.R., J.M.-S.), University of Oxford, UK; and US/MRC Centre for Molecular and Cellular Biology (J.M.-S.), University of Stellenbosch Health Sciences Faculty, Tygerberg, South Africa.
Correspondence to Hugh Watkins, Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX2 8AF, UK. E-mail hugh.watkins{at}cardiov.ox.ac.uk
This Review is part of a thematic series on Myocyte Intra- and Extrasarcomeric Structural Proteins, which includes the following articles:
The Giant Protein Titin: A Major Player in Myocardial Mechanics, Signaling, and Disease
The Dystrophin Glycoprotein Complex: Signaling Strength and Integrity for the Sarcolemma
Cardiac Myosin Binding Protein C: Its Role in Physiology and Disease
David Kass Editor
Myosin binding protein-C (MyBP-C) is a thick filament–associated protein localized to the crossbridge-containing C zones of striated muscle sarcomeres. The cardiac isoform is composed of eight immunoglobulin I–like domains and three fibronectin 3–like domains and is known to be a physiological substrate of cAMP-dependent protein kinase. MyBP-C contributes to thick filament structure via interactions at its C-terminus with the light meromyosin section of the myosin rod and with titin. The protein also has a role in the regulation of contraction, due to the binding of its N-terminus to the subfragment-2 portion of myosin, which reduces actomyosin ATPase activity; phosphorylation abolishes this interaction, resulting in release of the "brake" on crossbridge cycling. Several structural models of the interaction of MyBP-C with myosin have been proposed, although its precise arrangement on the thick filament remains to be elucidated. Mutations in the gene encoding cardiac MyBP-C are a common cause of hypertrophic cardiomyopathy, and this has led to increased interest in the protein’s function. Investigation of disease-causing mutations in domains with unknown function has led to further insights into the mechanism of cMyBP-C action. This Review aims to collate the published data on those aspects of MyBP-C that are well characterized and to consider new and emerging data that further define its structural and regulatory roles and its arrangement in the sarcomere. We also speculate on the mechanisms by which hypertrophic cardiomyopathy–causing truncation and missense mutations affect the normal functioning of the sarcomere.
Key Words: cardiac myosin binding protein-C • hypertrophic cardiomyopathy • sarcomere • contractility
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