The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations

Abstract

Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in β-cardiac myosin and myosin-binding protein-C (MyBP-C). Changes in the contractile parameters of myosin measured so far do not explain the clinical hypercontractility caused by such mutations. We propose that hypercontractility is due to an increase in the number of myosin heads (S1) that are accessible for force production. In support of this hypothesis, we demonstrate myosin tail (S2)-dependent functional regulation of actin-activated human β-cardiac myosin ATPase. In addition, we show that both S2 and MyBP-C bind to S1 and that phosphorylation of either S1 or MyBP-C weakens these interactions. Importantly, the S1-S2 interaction is also weakened by four myosin HCM-causing mutations but not by two other mutations. To explain these experimental results, we propose a working structural model involving multiple interactions, including those with myosin’s own S2 and MyBP-C, that hold myosin in a sequestered state.

A Mixed-Kinetic Model Describes Unloaded Velocities of Smooth, Skeletal, and Cardiac Muscle Myosin Filaments in Vitro

“…The results of this study and previous studies (5,6,(18)(19)(20) suggest that different muscles may operate primarily in different kinetic regimes depending on the effective N, which presumably would change as the muscle transitions from relaxed to partial and full activation. Also, L may not be a constant in muscle but could be modulated by effectors that interact with the S2 domain, such as myosin binding protein C. Similarly, phosphorylation of the regulatory light chain is thought to weaken the interactions of the myosin heads with the S2 domain (49), a region that has recently been shown to be important in mutations involved in hereditary heart disease (7,50). We suggest that our approach can reveal the mechanochemical mechanisms underlying such perturbations.…”

“…For example, myosin subfragments such as S1 and heavy meromyosin (HMM), which lack all or a portion of the tail domain, can be studied using the A/M m assay. These subfragments are soluble and easier to express than full-length myosin and thus allow the study of the effects of mutations (7)(8)(9)(10)(11). In contrast, the M f /A assay requires myosin with a full-length tail domain, the C-terminal portion of which contains the structural requirements for self-assembly into filaments.…”

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

“…Among the myofilament proteins, mutations in β‐myosin heavy chain (β‐MHC) and cardiac myosin binding protein‐C (cMyBPC) account for ≈80% of all known cases of inherited HCM 10, 11. This observation emphasizes the importance of understanding the mechanisms that underlie cardiac hypercontractility caused by MHC and cMyBPC mutations, and how these functional defects can be reversed or normalized using genetic or pharmacological approaches 12.…”

“…Missense mutations in human cardiac β‐MHC result in variable effects on contractile function including reduced13, 14 or enhanced intrinsic force generation15, 16; decreased14, 16 or enhanced15 myosin ATPase activity; and accelerated13, 15, 17 or slowed16 actin sliding velocities. Importantly, recent data show that HCM‐causing mutations in β‐MHC that cause hypercontractility weaken myosin's S1‐S2 intradomain interactions, thus effectively increasing the total number of myosin heads that can interact with actin during systole,11 thereby chronically elevating left ventricular ejection fraction 5, 18. Thus, recent studies have attempted to normalize HCM‐related hypercontractility by directly targeting the myosin motor rather than using β‐blockers and calmodulin antagonists, which may trigger the activation of unwanted signaling pathways 19, 20.…”

Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology

“…However, more recently, a weak interaction between the N-terminus of MyBP-C and the myosin regulatory light chain has been described. Residing in the C0 domain, this may represent a unique cardiac- specific interaction between myosin and MyBP-C [26, 27]. These interactions likely stabilize the myosin super-relaxed state, also known as the OFF state, thereby modulating muscle contractility [28-30].…”