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(Circulation Research. 2004;95:930.)
© 2004 American Heart Association, Inc.

Cellular Biology

Binding of Myosin Binding Protein-C to Myosin Subfragment S2 Affects Contractility Independent of a Tether Mechanism

Samantha P. Harris, Elena Rostkova, Mathias Gautel, Richard L. Moss

From the Department of Bioengineering (S.P.H.), University of Washington, Seattle, Wash; Cardiovascular and Randall Divisions (E.R., M.G.), King’s College London, London, UK; and the Department of Physiology (R.L.M.), University of Wisconsin, Madison.

Correspondence to Samantha Harris, PhD, Department of Bioengineering, Box 357962, University of Washington, Seattle, WA 98195. E-mail spharris{at}u.washington.edu

Mutations in the cardiac myosin binding protein-C gene (cMyBP-C) are among the most prevalent causes of inherited hypertrophic cardiomyopathy. Although most cMyBP-C mutations cause reading frameshifts that are predicted to encode truncated peptides, it is not known if or how expression of these peptides causes disease. One possibility is that because the N-terminus contains a unique binding site for the S2 subfragment of myosin, shortened cMyBP-C peptides could directly affect myosin contraction by binding to S2. To test this hypothesis, we compared the effects of a C1C2 protein containing the myosin S2 binding site on contractile properties in permeablized myocytes from wild-type and cMyBP-C knockout mice. In wild-type myocytes, the C1C2 protein reversibly increased myofilament Ca²⁺ sensitivity of tension, but had no effect on resting tension. Identical results were observed in cMyBP-C knockout myocytes where C1C2 increased Ca²⁺ sensitivity of tension with the half-maximal response elicited at 5 µmol/L C1C2. Maximum force was not affected by C1C2. However, phosphorylation of C1C2 by cAMP-dependent protein kinase reduced its ability to increase Ca²⁺ sensitivity. These results demonstrate that binding of the C1C2 peptide to S2 alone is sufficient to affect myosin contractile function and suggest that regulated binding of cMyBP-C to myosin S2 by phosphorylation directly influences myofilament Ca²⁺ sensitivity.

Key Words: Ca²⁺ sensitization • myocardial contractility • cardiac muscle • cardiac myocytes • cardiomyopathy • transgenic mice

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