Myosin Binding Protein C, a Phosphorylation-Dependent Force Regulator in Muscle That Controls the Attachment of Myosin Heads by Its Interaction With Myosin S2
作者:
Gudrun Kunst,
Kai Kress,
Mathias Gruen,
Dietmar Uttenweiler,
Mathias Gautel,
Rainer Fink,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 2000)
卷期:
Volume 86,
issue 1
页码: 51-51
ISSN:0009-7330
年代: 2000
出版商: OVID
关键词: myosin binding protein C;familial hypertrophic cardiomyopathy;protein phosphorylation;contraction regulation
数据来源: OVID
摘要:
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 istris-phosphorylated by cAMP-dependent protein kinase (cAPK) on &bgr;-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.
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