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.

Nanomechanical phenotypes in cMyBP-C mutants that cause hypertrophic cardiomyopathy

“…The modulatory mechanisms of cMyBP-C on contraction are complex and far from being completely understood. While the C8-C10 C-terminal domains of cMyBP-C play a structural role providing strong anchorage to the thick filament, the C0-C2 N-terminal fragments can bind both actin filaments and myosin globular heads resulting in sophisticated control of their activity through direct mechanical load (Figure 1b) or via conformational changes that are dependent on phosphorylation and calcium levels 15 . In this highly intricate regulatory landscape, several possibilities can be envisioned by which altered cMyBP-C nanomechanics, as detected here for R495W and R502Q (Figures 4d, 5c), can perturb sarcomere function.…”

“…Let us first consider a purely mechanical scenario. Current models on cMyBP-C modulation of sarcomere contraction state that the central region of the protein is subject to end-to-end mechanical force that results in a viscous drag opposing contraction (Figure 1b) 15,21,[23][24][65][66] . This drag force depends on cMyBP-C stiffness.…”

“…In sarcomeres, myosin heads use the energy coming from ATP hydrolysis to extend from the myosin backbone in the thick filaments, establish cross-bridges with the neighboring actin thin filaments and generate ~10-nm power strokes that propel the thin filaments past the thick ones leading to muscle contraction (Figure 1b) 4,8,[10][11][12] . Cardiac myosin-binding protein C (cMyBP-C) is a wellknown negative modulator of sarcomere contraction by complex mechanisms that are not fully understood [13][14][15] . This multidomain protein is located in the C-zone of the sarcomere, grouped in nine regularly-spaced transverse stripes that are 43 nm apart from each other 16 .…”

“…cMyBP-C's Cterminal C8-C10 domains run axially along the thick filament, interacting both with the myosin backbone and titin. The central and N-terminal domains of the protein extend radially from the thick filament towards the thin filament located ~23-nm away (Figure 1) 13,[15][16][17][18][19][20] . In this geometry, the N-terminal domains of cMyBP-C can interact both with the myosin head region and with the Comparison of a healthy heart and an HCM counterpart, which shows thicker left ventricular walls and reduced left ventricle volume.…”

“…Hence, how cMyBP-C tethers respond to mechanical load [24][25][26] can be fundamental for its modulatory role on sarcomere power generation. MYH7 and MYBPC3, which codify for β-myosin heavy chain and cMyBP-C, respectively, are the most frequently mutated genes in HCM, accounting for 80% of cases 13,15,19 . A large proportion of pathogenic variants in MYBPC3 result in cMyBP-C truncations that induce HCM via reduction in total cMyBP-C content (protein haploinsufficiency) 4,13,[28][29][30][31][32][33][34] .…”