Hypertrophic cardiomyopathy and the myosin mesa: viewing an old disease in a new light

Abstract

The sarcomere is an exquisitely designed apparatus that is capable of generating force, which in the case of the heart results in the pumping of blood throughout the body. At the molecular level, an ATP-dependent interaction of myosin with actin drives the contraction and force generation of the sarcomere. Over the past six decades, work on muscle has yielded tremendous insights into the workings of the sarcomeric system. We now stand on the cusp where the acquired knowledge of how the sarcomere contracts and how that contraction is regulated can be extended to an understanding of the molecular mechanisms of sarcomeric diseases, such as hypertrophic cardiomyopathy (HCM). In this review we present a picture that combines current knowledge of the myosin mesa, the sequestered state of myosin heads on the thick filament, known as the interacting-heads motif (IHM), their possible interaction with myosin binding protein C (MyBP-C) and how these interactions can be abrogated leading to hyper-contractility, a key clinical manifestation of HCM. We discuss the structural and functional basis of the IHM state of the myosin heads and identify HCM-causing mutations that can directly impact the equilibrium between the ‘on state’ of the myosin heads (the open state) and the IHM ‘off state’. We also hypothesize a role of MyBP-C in helping to maintain myosin heads in the IHM state on the thick filament, allowing release in a graded manner upon adrenergic stimulation. By viewing clinical hyper-contractility as the result of the destabilization of the IHM state, our aim is to view an old disease in a new light.

Myosin motor domains carrying mutations implicated in early or late onset Hypertrophic Cardiomyopathy have similar properties

“…Such motors are likely to be further stabilized by interactions with both the backbone of the thick filament and MyBPC (Alamo et al, 2017). Myosin mutations that destabilize the off-state would make more heads available and lead to a hyper-contractile state, thought by many to be the precursor to HCM (Alamo et al, 2017;Trivedi, Adhikari, Sarkar, Ruppel, & Spudich, 2017). The interaction between the off and on state of myosin is postulated to be regulated by phosphorylation of the RLC, or the MyBPC, mechanical strain on the thick filament, and possibly calcium (Linari et al, 2015;Mohamed, Dignam, & Schlender, 1998;Previs et al, 2016;Toepfer et al, 2013) Destabilization of the off-state could occur by reducing motor-motor, motor-backbone or motor-MyBPC interactions.…”

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

“…Importantly, it is also interesting to note that the magnitudes of Myk461‐induced force depression are less pronounced in the KO myocardium when compared with WT myocardium especially at low Ca 2+ activations, but are nearly equivalent in both groups at high Ca 2+ activations (Figure 3C to 3F). This diminished impact of Myk461 on force depression in the KO myocardium is likely because of the fact that cMyBPC normally tethers to myosin heads and prevents binding of myosin heads to actin,10, 51, 52 while the absence of cMyBPC relieves this physical constraint on myosin heads, allowing the myosin heads to move away from the thick filament backbone and towards actin binding sites, thus enhancing acto‐myosin XB formation 31. On the other hand, Myk461 has not been shown to prevent the binding of myosin heads to actin per se, but rather, acts to reduce the number of XBs transitioning from a weakly to a strongly bound state 22.…”

The molecular basis of hypercontractility caused by the hypertrophic cardiomyopathy mutations R403Q and R663H

“…An attractive model is that the equilibrium of myosin between the IHM and the open state in cardiac fibers regulates the power generation of the sarcomere by controlling Na (7,16).…”

“…Here we show this is even more dramatically true for the R663H HCM mutation, which leads to virtually no changes in the fundamental contractile behaviors of human ß-cardiac myosin. Our recent work has focused on the 'unifying hypothesis' (7,16) that most HCM mutations may be releasing myosin heads from a sequestered state, thus increasing the number of heads functionally accessible for interaction with actin (Na). The IHM state is the likely structural analog of this sequestered state (9,10), which fits with the findings that the majority of HCM mutations are found on the myosin mesa, proximal S2, the converter domain, and other key intramolecular interaction sites in the IHM structure (12,13,33).…”