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

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)930-936
Number of pages7
JournalCirculation Research
Volume95
Issue number9
DOIs
StatePublished - Oct 29 2004
Externally publishedYes

Keywords

  • Ca sensitization
  • Cardiac muscle
  • Cardiac myocytes
  • Cardiomyopathy
  • Myocardial contractility
  • Transgenic mice

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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