© 2000 American Heart Association, Inc.
Cellular Biology |
Myosin Binding Protein C, a Phosphorylation-Dependent Force Regulator in Muscle That Controls the Attachment of Myosin Heads by Its Interaction With Myosin S2
From the Department of Anaesthesiology (G.K.) and the Institute of Physiology and Pathophysiology (K.R.K., D.U., R.H.A.F.), University of Heidelberg, Heidelberg, Germany; Max-Planck-Institute for Molecular Physiology (M. Gruen, M. Gautel), Department of Physical Biochemistry, Dortmund, Germany.
Correspondence to Mathias Gautel, Max-Planck-Institute for Molecular Physiology, Department of Physical Biochemistry, Postfach 500247, 44202 Dortmund, Germany. E-mail mathias.gautel{at}mpi-dortmund.mpg.de
Abstract—Myosin binding protein C (MyBP-C) is one of the major sarcomeric proteins involved in the pathophysiology of familial hypertrophic cardiomyopathy (FHC). The cardiac isoform is tris-phosphorylated by cAMP-dependent protein kinase (cAPK) on ß-adrenergic stimulation at a conserved N-terminal domain (MyBP-C motif), suggesting a role in regulating positive inotropy mediated by cAPK. Recent data show that the MyBP-C motif binds to a conserved segment of sarcomeric myosin S2 in a phosphorylation-regulated way. Given that most MyBP-C mutations that cause FHC are predicted to result in N-terminal fragments of the protein, we investigated the specific effects of the MyBP-C motif on contractility and its modulation by cAPK phosphorylation. The diffusion of proteins into skinned fibers allows the investigation of effects of defined molecular regions of MyBP-C, because the endogenous MyBP-C is associated with few myosin heads. Furthermore, the effect of phosphorylation of cardiac MyBP-C can be studied in a defined unphosphorylated background in skeletal muscle fibers only. Triton skinned fibers were tested for maximal isometric force, Ca2+/force relation, rigor force, and stiffness in the absence and presence of the recombinant cardiac MyBP-C motif. The presence of unphosphorylated MyBP-C motif resulted in a significant (1) depression of Ca2+-activated maximal force with no effect on dynamic stiffness, (2) increase of the Ca2+ sensitivity of active force (leftward shift of the Ca2+/force relation), (3) increase of maximal rigor force, and (4) an acceleration of rigor force and rigor stiffness development. Tris-phosphorylation of the MyBP-C motif by cAPK abolished these effects. This is the first demonstration that the S2 binding domain of MyBP-C is a modulator of contractility. The anchorage of the MyBP-C motif to the myosin filament is not needed for the observed effects, arguing that the mechanism of MyBP-C regulation is at least partly independent of a "tether," in agreement with a modulation of the head-tail mobility. Soluble fragments occurring in FHC, lacking the spatial specificity, might therefore lead to altered contraction regulation without affecting sarcomere structure directly.
Key Words: myosin binding protein C • familial hypertrophic cardiomyopathy • protein phosphorylation • contraction regulation
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