Cardiac Myosin-binding protein C modulates the tuning of the molecular motor in the heart.
Cardiac myosin binding protein C (cMyBP-C) is an important regulator of cardiac contractility. Its precise effect on myosin cross-bridges (CBs) remains unclear. Using a cMyBP-C(-/-) mouse model, we determined how cMyBP-C modulates the cyclic interaction of CBs with actin. From papillary muscle mechanics, CB characteristics were provided using A. F. Huxley's equations. The probability of myosin being weakly bound to actin was higher in cMyBP-C(-/-) than in cMyBP-C(+/+). However, the number of CBs in strongly bound, high-force generated state and the force generated per CB were lower in cMyBP-C(-/-). Overall CB cycling and the velocity of CB tilting were accelerated in cMyBP-C(-/-). Taking advantage of the presence of cMyBP-C in cMyBP-C(+/+) myosin solution but not in cMyBP-C(-/-), we also analyzed the effects of cMyBP-C on the myosin-based sliding velocity of actin filaments. At baseline, sliding velocity and the relative isometric CB force, as determined by the amount of alpha-actinin required to arrest thin filament motility, were lower in cMyBP-C(-/-) than in cMyBP-C(+/+). cAMP-dependent protein kinase-mediated cMyBP-C phosphorylation further increased the force produced by CBs. We conclude that cMyBP-C prevents inefficient, weak binding of the myosin CB to actin and has a critical effect on the power-stroke step of the myosin molecular motor.
Lecarpentier
Yves
Y
INSERM, U689, Cardiovascular Research Center, Paris, France.
Vignier
Nicolas
N
Oliviero
Patricia
P
Guellich
Aziz
A
Carrier
Lucie
L
Coirault
Catherine
C
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D003198:Computer Simulation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D020409:Molecular Motor Proteins / Q000502:physiology*; D009119:Muscle Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D020409:Molecular Motor Proteins; D000099163:Myosin Binding Protein C