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Titolo:
Myosin binding protein C, a phosphorylation-dependent force regulator in muscle that controls the attachment of myosin heads by its interaction with myosin S2
Autore:
Kunst, G; Kress, KR; Gruen, M; Uttenweiler, D; Gautel, M; Fink, RHA;
Indirizzi:
Max Planck Inst Mol Physiol, Dept Phys Biochem, D-44202 Dortmund, Germany Max Planck Inst Mol Physiol Dortmund Germany D-44202 2 Dortmund, Germany Univ Heidelberg, Dept Anaesthesiol, Heidelberg, Germany Univ Heidelberg Heidelberg Germany pt Anaesthesiol, Heidelberg, Germany Univ Heidelberg, Inst Physiol & Pathophysiol, Heidelberg, Germany Univ Heidelberg Heidelberg Germany & Pathophysiol, Heidelberg, Germany
Titolo Testata:
CIRCULATION RESEARCH
fascicolo: 1, volume: 86, anno: 2000,
pagine: 51 - 58
SICI:
0009-7330(20000107)86:1<51:MBPCAP>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; RABBIT SKELETAL-MUSCLE; CARDIAC-MUSCLE; MYOFIBRILLAR PROTEIN; LENGTH DEPENDENCE; CA2+ SENSITIVITY; ATPASE ACTIVITY; IONIC-STRENGTH; SITE MUTATION; FAST-TWITCH;
Keywords:
myosin binding protein C; familial hypertrophic cardiomyopathy; protein phosphorylation; contraction regulation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
58
Recensione:
Indirizzi per estratti:
Indirizzo: Gautel, M Max Planck Inst Mol Physiol, Dept Phys Biochem, Postfach 500247,D-44202 Dortmund, Germany Max Planck Inst Mol Physiol Postfach 500247 Dortmund Germany D-44202
Citazione:
G. Kunst et al., "Myosin binding protein C, a phosphorylation-dependent force regulator in muscle that controls the attachment of myosin heads by its interaction with myosin S2", CIRCUL RES, 86(1), 2000, pp. 51-58

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 beta-adrenergic stimulation at a conserved N-terminal domain(MyBP-C motif), suggesting a role in regulating positive inotropy mediatedby 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-Cmotif 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 ofCa2+-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 accelerationof 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 atleast 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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Documento generato il 03/12/20 alle ore 16:06:03