Altered interactions between cardiac myosin binding protein-c and α-cardiac actin variants associated with cardiomyopathies

Abstract

The two genes most commonly associated with mutations linked to hypertrophic or dilated cardiomyopathies are β-myosin and cardiac myosin binding protein-C (cMyBP-C). Both of these proteins interact with cardiac actin (ACTC). Currently there are 16 ACTC variants that have been found in patients with HCM or DCM. While some of these ACTC variants exhibit protein instability or polymerization-deficiencies that might contribute to the development of disease, other changes could cause changes in protein-protein interactions between sarcomere proteins and ACTC. To test the hypothesis that changes in ACTC disrupt interactions with cMyBP-C, we examined the interactions between seven ACTC variants and the N-terminal C0C2 fragment of cMyBP-C. We found there was a significant decrease in binding affinity (increase in Kd values) for the A331P and Y166C variants of ACTC. These results suggest that a change in the ability of cMyBP-C to bind actin filaments containing these ACTC protein variants might contribute to the development of disease. These results also provide clues regarding the binding site of the C0C2 fragment of cMyBP-C on F-actin.

The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy

“…The other major site in the sarcomere for mutations is a regulatory protein known as myosin-binding protein C (MyBP-C). MyBP-C is thought to put a break on the contraction of the muscle, which can be alleviated by its phosphorylation [19,26–28]. A smaller but significant set of mutations are found in the tropomyosin–troponin (Tm–Tn) complex.…”

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin

“…There is good evidence that domains of MyBP-C near the N terminus bind to the regulated actin filament, whereas its C terminus binds to the myosin thick filament backbone (Fig. 2), playing a regulatory role in muscle contraction (Chow et al, 2014;Kensler et al, 2011;van Dijk et al, 2014). MyBP-C is in the A-band region of the sarcomere in close proximity to the myosin heads (Fig.…”

“…MyBP-C is thought to put a break on the contraction of the muscle, which can be regulated by its phosphorylation (Chow et al, 2014;Kensler et al, 2011;Seidman and Seidman, 2000;van Dijk et al, 2014). There is good evidence that domains of MyBP-C near the N terminus bind to the regulated actin filament, whereas its C terminus binds to the myosin thick filament backbone (Fig.…”

“…There is good evidence that domains of MyBP-C near the N terminus bind to the regulated actin filament while its C terminus binds to the myosin thick filament backbone (Fig. 2), thus playing a regulatory role in muscle contraction (Chow et al, 2014;Kensler et al, 2011;van Dijk et al, 2014). Studies also suggest that MyBP-C binds to myosin S2, the coiled-coil domain just C-terminal to the globular S1 head, as well as to the regulatory light chain (RLC) of the myosin S1 (Harris et al, 2004;Kampourakis et al, 2014;Pfuhl and Gautel, 2012;Ratti et al, 2011).…”

“…The other major site in the sarcomere for HCM-causing mutations is a regulatory protein known as myosin binding protein-C (MyBP-C). MyBP-C is thought to put a break on the contraction of the muscle, which can be regulated by its phosphorylation (Chow et al, 2014;Kensler et al, 2011;Seidman and Seidman, 2000;van Dijk et al, 2014). A smaller but significant set of mutations are found in the tropomyosintroponin complex.…”