Post-translational control of cardiac hemodynamics through myosin binding protein C

Abstract

Cardiac myosin binding protein C (cMyBP-C) is an integral sarcomeric protein that associates with the thick, thin, and titin filament systems in the contractile apparatus. Three different isoforms of MyBP-C exist in mammalian muscle: slow skeletal (MyBPC1), fast skeletal (MyBP-C2, with several variants), and cardiac (cMyBP-C). Genetic screening studies show that mutations in MYBPC3 occur frequently and are responsible for as many as 30-35 % of identified cases of familial hypertrophic cardiomyopathy. The function of cMyBP-C is stringently regulated by its post-translational modification. In particular, the addition of phosphate groups occurs with high frequency on certain serine residues that are located in the cardiac-specific regulatory M domain. Phosphorylation of this domain has been extensively studied in vitro and in vivo. Phosphorylation of the M domain can regulate the manner in which actin and myosin interact, affecting the cross bridge cycle and ultimately, cardiac hemodynamics.

Figure 1

Structure of cMyBP-C. Schematic diagram showing the protein’s restricted sarcomeric location (green lines, top), its domain structure with 8 IgG domains (green), 3 fibronectin domains (light blue) and the cardiac specific M domain (red), with the three phosphorylatable serines discussed in this review indicated. The approximate locations of the binding sites for myosin heavy chain (head and rod regions; S2 and LMM, respectively) are also shown as well as the binding sites for titin and actin.

Figure 2

Schematic description of the effects on cardiac hemodynamics when the three serines are mutated either to non-phosphorylatable alanine or the phosphomimetic aspartate. Heart function was analyzed by invasive catheterization. Detailed data are presented in [13]. Green, yellow and red indicates normal, moderately compromised and poor cardiac function, respectively.