Signaling and myosin-binding protein C

Abstract

Myosin-binding protein C (MyBP-C) is a thick filament protein consisting of 1274 amino acid residues (149 kDa) that was identified by Starr and Offer over 30 years ago as a contaminant present in a preparation of purified myosin. Since then, numerous studies have defined the muscle-specific isoforms, the structure, and the importance of the proteins in normal striated muscle structure and function. Underlying the critical role the protein plays, it is now apparent that mutations in the cardiac isoform (cMyBP-C) are responsible for a substantial proportion (30-40%) of genotyped cases of familial hypertrophic cardiomyopathy. Although generally accepted that MyBP-C can interact with all three filament systems within the sarcomere (the thick, thin, and titin filaments), the exact nature of these interactions and the functional consequences of modified binding remain obscure. In addition to these structural considerations, cMyBP-C can serve as a point of convergence for signaling processes in the cardiomyocyte via post-translational modifications mediated by kinases that phosphorylate residues in the cardiac-specific isoform sequence. Thus, cMyBP-C is a critical nodal point that has both important structural and signaling roles and whose modifications are known to cause significant human cardiac disease.

FIGURE 1.

Sarcomere location of MyBP-C. The electron micrograph was taken from the 1972 report on the Cold Spring Harbor Symposia on Quantitative Biology (1) and is used with permission of the Cold Spring Harbor Press. Shown is an electron micrograph of glycerinated rabbit psoas muscle that was labeled with antiserum developed against MyBP-C: an area contained within the MyBP-C staining region is magnified so that the serial lines of the immunoreactive material are apparent. Shown below the micrograph is a schematic diagram of a sarcomere that highlights the three filament systems: the thick filament, which contains myosin; the thin filament, which contains actin; and the third filament, titin. MyBP-C is located on each side of the M-band and may associate with myosin in a collar-like structure consisting of a trimer (48).

FIGURE 2.

Domain structure of cMyBP-C. Shown is a schematic diagram outlining the different domains and their proposed interactions with the sarcomere filament systems. The eight Ig-like domains (in green) and three fibronectin-like domains (in orange) are numbered sequentially. The cardiac-specific insert near the N terminus is expanded to show the human and mouse sequences, and the three confirmed and conserved phosphorylatable serines within this region are boxed, with the kinases that are currently thought to act upon them indicated below. The Pro/Ala-rich region is also shown, but this is highly divergent between species (43), implying that the actin binding characteristics of cMyBP-C may be species-dependent. LMM, light meromyosin region of the myosin rod.