Cardiac myosin binding protein-C as a central target of cardiac sarcomere signaling: a special mini review series

Abstract

Cardiac myosin binding protein-C (cMyBP-C) is a cardiac-specific thick filament assembly, accessory, and regulatory protein. Physiologically, it is a key regulator of cardiac contractility. With more than 200 mutations in the cMyBP-C gene directly linked to the development of cardiomyopathy and heart failure, cMyBP-C clearly plays a critical role in heart function. At baseline, cMyBP-C is highly phosphorylated, a condition required for normal cardiac function. However, the level of cMyBP-C phosphorylation is significantly decreased during heart failure, indicating that the level of cMyBP-C phosphorylation is directly linked to signaling and cardiac function. Early studies indicated that cMyBP-C interacts with myosin and titin, whereas studies now show that it also interacts with thin filament proteins. However, the exact role(s) of cMyBP-C in the heart remain(s) to be elucidated. As such, we invited experts in the field of cardiac muscle to identify and address key issues related to cMyBP-C by contributing a mini review on such topics as structure, function, regulation, cardiomyopathy, proteolysis, and gene therapy. Starting from this issue, Pflügers Archiv European Journal of Physiology will publish two invited mini review articles each month to discuss the most recent advances in the study of cMyBP-C.

Figure 1. Schematic diagram of cMyBP-C localization in the heart

Cardiac striated muscle in the myocardium is predominantly made up of myofibrils. (A) The sarcomere, which is the functional unit of myofibrils, consists of thick and thin contractile filament proteins. The thick filament proteins are titin, myosin and cMyBP-C, whereas the thin filament proteins are actin, α-TM, cTnT, cTnI and cTnC. The cMyBP-C protein is exclusively expressed in the heart, and it transversely connects both thick and thin filament proteins. (B) cMyBP-C is comprised of 8 immunoglobulin (Ig) and 3 fibronectin type III domains, numbered from the N-terminus as Motifs 0 to 10. In addition, a proline-alanine-rich region is found between the C0 and C1 domains, as well as a phosphorylation motif (M domain), which is found between the C1 and C2 domains. N-terminal regions (C0-C2 domains) interact with thin filament proteins such as actin and thick filament proteins such as myosin S2. C-terminal regions (C8-C10 domains) interact with the thick filament protein titin and the LMM hinge regions.