Myosin molecular motors play crucial, dynamic roles in most cellular processes, including contraction, movement, and shape change. A variety of diseases owe their origins to defects in the myosin family of molecular motors. A prime example is inherited familial hypertrophic cardiomyopathy (HCM), which leads to hyper-contractility of the heart. HCM results from single missense mutations in various cardiac muscle proteins, with mutations in ?-cardiac myosin accounting for about 40% of these cases. HCM is not rare, affecting 1 out of 500 people. Current therapeutic interventions for cardiomyopathies are limited to symptomatic relief, in large part because the molecular underpinnings of the disease ? how mutations affect the biomechanical interaction of myosin with its sarcomeric partners, and thus sarcomeric force, velocity, and power output ? are not well understood. Since HCM results from single residue mutations in human ?-cardiac myosin, it is imperative to study the human protein rather than cardiac myosins from other species, where there are numerous residue differences from human throughout the protein. To fully understand the system, it was important to begin with the simplest reconstituted system to elucidate the effects of these mutations on power output. We have made substantial progress in that regard over the last few years studying just the myosin motor domain with its essential light chain and its interaction with pure actin filaments. Next it is important to build on the complexity of the reconstituted system, incorporating a two-headed molecule that contains a phosphorylatable regulatory light chain, the calcium-regulatory proteins tropomyosin-troponin as part of the actin thin filament, and a second regulatory component, myosin binding protein-C. Thus, we will use this more complex reconstituted system and an array of assays to determine the biochemical and biomechanical changes in the human ?-cardiac myosin motor that result from a wide variety of HCM-causing mutations, in order to get a larger picture of the variety of mechanistic reasons for the observed clinical changes in contractility caused by these mutations.
Inherited familial cardiomyopathies affecting 1 out of 500 people result from missense mutations in various cardiac muscle proteins, with mutations in beta-cardiac myosin being one of the most common sources of this disease. Current therapies for cardiomyopathies are limited to symptomatic relief, in large part because it is not understood how these mutations affect the ability of the heart to contract at its most fundamental level. Our research will significantly enhance our understanding of the effects of disease causing mutations on the fundamental contractile properties of the heart.
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