Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology

Abstract

The Myosin Binding Protein-C (MyBP-C) family is a group of sarcomeric proteins important for striated muscle structure and function. Comprising approximately 2% of the myofilament mass, MyBP-C has important roles in both contraction and relaxation. Three paralogs of MyBP-C are encoded by separate genes with distinct expression profiles in striated muscle. In mammals, cardiac MyBP-C is limited to the heart, and it is the most extensively studied owing to its involvement in cardiomyopathies. However, the roles of two skeletal paralogs, slow and fast, in muscle biology remain poorly characterized. Nonetheless, both have been recently implicated in the development of skeletal myopathies. This calls for a better understanding of their function in the pathophysiology of distal arthrogryposis. This review characterizes MyBP-C as a whole and points out knowledge gaps that still remain with respect to skeletal MyBP-C.

Keywords: Distal arthrogryposis; MYBPC; Myofilament; Sarcomere; Striated muscle.

Figure 1.. The three types of muscle.

Striated cardiac muscle is expressed exclusively within the heart. Skeletal muscles are also striated, but under voluntary control. Smooth muscle lines the walls of hollow organs and vessels and is under the control of the autonomic nervous system

Figure 2.. Striated muscle ultrastructure and the myofilament.

A, Electron micrograph of the cardiac myofilament. B, Schematic diagram illustrating the structure of the cardiac myofilament. Myofilament proteins, such as thick filament proteins (titin, myosin, myosin binding protein-C, light chains) and thin filament proteins (actin, tropomyosin, troponin I, C and T), are shown.

Figure 3.. Domain structure of the three paralogs of MyBP-C.

Immunoglobulin domains are shown in orange circles, while fibronectin-III domains are shown in grey hexagons. The proline-alanine (P/A)-rich linker is shown in yellow, and the M-domain is shown as a blue circle. Phosphorylation sites are shown as purple stripes. ssMyBP-C is shown in A with its three phosphorylation sites in the P/A and one within the M-domain. B shows the domain structure of fsMyBP-C. cMyBP-C has an additional N-terminal immunoglobulin domain (C0), four phosphorylation sites in the M-domain, one phosphorylation site in the P/A linker, and a 28 novel amino acid insertion in the C5 domain (red stripe), C.

Figure 4.. Location of skeletal MyBP-C mutations.

The many MYBPC1 mutations shown in A. Note that the L295R mutation was discovered in a 2-week-old female calf. The two co-discovered MYBPC2 mutations are shown in fsMyBP-C in B.