Phosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments.
Cardiac myosin binding protein C (cMyBP-C) has a key regulatory role in cardiac contraction, but the mechanism by which changes in phosphorylation of cMyBP-C accelerate cross-bridge kinetics remains unknown. In this study, we isolated thick filaments from the hearts of mice in which the three serine residues (Ser273, Ser282, and Ser302) that are phosphorylated by protein kinase A in the m-domain of cMyBP-C were replaced by either alanine or aspartic acid, mimicking the fully nonphosphorylated and the fully phosphorylated state of cMyBP-C, respectively. We found that thick filaments from the cMyBP-C phospho-deficient hearts had highly ordered cross-bridge arrays, whereas the filaments from the cMyBP-C phospho-mimetic hearts showed a strong tendency toward disorder. Our results support the hypothesis that dephosphorylation of cMyBP-C promotes or stabilizes the relaxed/superrelaxed quasi-helical ordering of the myosin heads on the filament surface, whereas phosphorylation weakens this stabilization and binding of the heads to the backbone. Such structural changes would modulate the probability of myosin binding to actin and could help explain the acceleration of cross-bridge interactions with actin when cMyBP-C is phosphorylated because of, for example, activation of β1-adrenergic receptors in myocardium.
Department of Anatomy and Neurobiology, University of Puerto Rico Medical School, San Juan, PR 00936; robert.kensler@upr.edu.
Robert W
RW
Kensler
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655.
Roger
R
Craig
Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
Richard L
RL
Moss
D000199:Actins / Q000378:metabolism; D000818:Animals; D024722:Cardiac Myosins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000502:physiology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D000099163:Myosin Binding Protein C
D000199:Actins; D024722:Cardiac Myosins; D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D000099163:Myosin Binding Protein C
cMyBP-C; cardiac myosin binding protein C; cardiac myosin binding protein C function; cardiac thick filament; cardiac thick filament structure