MyBP-C: one protein to govern them all

Abstract

The heart is an extraordinarily versatile pump, finely tuned to respond to a multitude of demands. Given the heart pumps without rest for decades its efficiency is particularly relevant. Although many proteins in the heart are essential for viability, the non-essential components can attract numerous mutations which can cause disease, possibly through alterations in pumping efficiency. Of these, myosin binding protein C is strongly over-represented with ~ 40% of all known mutations in hypertrophic cardiomyopathy. Therefore, a complete understanding of its molecular function in the cardiac sarcomere is warranted. In this review, we revisit contemporary and classical literature to clarify both the current standing of this fast-moving field and frame future unresolved questions. To date, much effort has been directed at understanding MyBP-C function on either thick or thin filaments. Here we aim to focus questions on how MyBP-C functions at a molecular level in the context of both the thick and thin filaments together. A concept that emerges is MyBP-C acts to govern interactions on two levels; controlling myosin access to the thin filament by sequestration on the thick filament, and controlling the activation state and access of myosin to its binding sites on the thin filament. Such affects are achieved through directed interactions mediated by phosphorylation (of MyBP-C and other sarcomeric components) and calcium.

Keywords: Cardiac; Contractility; Muscle contraction; Myosin binding protein C; cMyBP-C.

Fig. 1

Schematic diagram of full length slow skeletal (ss), fast skeletal (fs) and cardiac (c) MyBPC paralogs. Each isoform comprises three Fn3 domains and seven or eight Ig domains. The known binding partners and positions are indicated by the horizontal stripes below. Note the phosphorylation sites in the P/A and M domain of the ssMyBP-C and cMyBP-C paralogs are indicated by small black ellipses. The cMyBP-C has an additional 28 amino acid loop in the C5 domain

Fig. 2

Schematic diagram of half-sarcomere organisation. The A-band contains thick filaments and overlapping thin filaments, the C-zone is the region of the thick filament with MyBP-C present, and the D-zone has no MyBP-C. The I-band contains thin filaments and also titin, which leads from the Z-line into the thick filaments. These areas are shown with more detail below, highlighting the content of the thick filaments in zone C versus D. For clarity only every third myosin crown is shown, please refer to Fig. 3 for details on stoichiometry

Fig. 3

a The molecular arrangement of the thick filament in the C-zone. Three molecules of MyBP-C associate via their C-terminal regions with myosin S2 at every third crown (orange cylinders) leading to a 43 nm spacing between MyBP-C zones which matches the axial repeat. MyBP-C also interacts with myosin heads/neck through the N-terminal regions, although it is clear from the diagram that MyBP-C can possibly extend to other myosins in the 14.3 nm helical repeat therefore the precise myosin that interacts with MyBP-C is unknown. Discovering the hinge points of MyBP-C and the geometry of its arrangement on the thick filament will be integral for understanding how MyBP-C works. b Myosin can exist in two clear configurations, left (active. heads-unfolded), right (inactive, heads folded). MyBP-C can modulate these forms of myosin, although the mechanism and location of binding sites are not fully known. Image taken from (Trivedi et al. 2018)

Fig. 4

The interplay between the thick and thin filaments mediated by cMyBP-C. The relaxed state is represented as a continuum of thick filament and thin filament states, which are modulated by phosphorylation and/or force. In a completely relaxed condition very few C-zone heads are likely to be activated, at the other end of the spectrum with RLC, cMyBP-C phosphorylation, and force the number of heads ready for generating tension is maximized. Interestingly, even though phosphorylation of cMyBP-C releases heads from the thick filament, it prevents cMyBP-C interacting with the thin filament. The acute stage of activation, mediated by calcium binding to the thin filament, results in cross-bridge attachment and now cMyBP-C can reveal its second, modulatory role on contraction. The complexity of this process is grossly underestimated in this diagram, however the questions necessary to understand this process are revealed