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J. Biol. Chem., Vol. 281, Issue 47, 35846-35854, November 24, 2006

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Effects of the N-terminal Domains of Myosin Binding Protein-C in an in Vitro Motility Assay

EVIDENCE FOR LONG-LIVED CROSS-BRIDGES^*

From the Department of Bioengineering, University of Washington, Seattle, Washington 98195

Myosin binding protein-C (MyBP-C) is a thick-filament protein whose precise function within the sarcomere is not known. However, recent evidence from cMyBP-C knock-out mice that lack MyBP-C in the heart suggest that cMyBP-C normally slows cross-bridge cycling rates and reduces myocyte power output. To investigate possible mechanisms by which cMyBP-C limits cross-bridge cycling kinetics we assessed effects of recombinant N-terminal domains of MyBP-C on the ability of heavy meromyosin (HMM) to support movement of actin filaments using in vitro motility assays. Here we show that N-terminal domains of cMyBP-C containing the MyBP-C "motif," a sequence of 110 amino acids, which is conserved across all MyBP-C isoforms, reduced actin filament velocity under conditions where filaments are maximally activated (i.e. either in the absence of thin filament regulatory proteins or in the presence of troponin and tropomyosin and high [Ca²⁺]). By contrast, under conditions where thin filament sliding speed is submaximal (i.e. in the presence of troponin and tropomyosin and low [Ca²⁺]), proteins containing the motif increased filament speed. Recombinant N-terminal proteins also bound to F-actin and inhibited acto-HMM ATPase rates in solution. The results suggest that N-terminal domains of MyBP-C slow cross-bridge cycling kinetics by reducing rates of cross-bridge detachment.

Received for publication, July 21, 2006 , and in revised form, September 11, 2006.

^* This work supported by American Heart Association Grant SDG 0130557Z and National Institutes of Health Grant HL080367 (to S. P. H.) and by National Institutes of Health Grant HL61683 to (M. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Bioengineering, University of Washington, Box 355061, Seattle, WA 98195. Tel.: 206-685-1510; Fax: 206-685-3300; E-mail: spharris{at}u.washington.edu.

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