Kunst, Gudrun;
Kress, Kai R.;
Gruen, Mathias;
Uttenweiler, Dietmar;
Gautel, Mathias;
Fink, Rainer H. A.
Myosin Binding Protein C, a Phosphorylation-Dependent Force Regulator in Muscle That Controls the Attachment of Myosin Heads by Its Interaction With Myosin S2
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Medientyp:
E-Artikel
Titel:
Myosin Binding Protein C, a Phosphorylation-Dependent Force Regulator in Muscle That Controls the Attachment of Myosin Heads by Its Interaction With Myosin S2
Beteiligte:
Kunst, Gudrun;
Kress, Kai R.;
Gruen, Mathias;
Uttenweiler, Dietmar;
Gautel, Mathias;
Fink, Rainer H. A.
Beschreibung:
<jats:p>
<jats:italic>Abstract</jats:italic>
—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
<jats:italic>tris</jats:italic>
-phosphorylated by cAMP-dependent protein kinase (cAPK) on β-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, Ca
<jats:sup>2+</jats:sup>
/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 Ca
<jats:sup>2+</jats:sup>
-activated maximal force with no effect on dynamic stiffness, (2) increase of the Ca
<jats:sup>2+</jats:sup>
sensitivity of active force (leftward shift of the Ca
<jats:sup>2+</jats:sup>
/force relation), (3) increase of maximal rigor force, and (4) an acceleration of rigor force and rigor stiffness development.
<jats:italic>Tris</jats:italic>
-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.
</jats:p>