Jul 24, 2016

Beyond the myosin mesa: a potential unifying hypothesis on the underlying molecular basis of hyper-contractility caused by a majority of hypertrophic cardiomyopathy mutations

BioRxiv : the Preprint Server for Biology
Suman NagJames A Spudich

Abstract

Hypertrophic cardiomyopathy (HCM), the most commonly occurring inherited cardiovascular disease, is primarily caused by mutations in human β-cardiac myosin and myosin binding protein-C. It has been thought that such mutations in myosin increase the intrinsic force of the motor, its velocity of contraction, or its ATPase activity, giving rise to hyper-contractility. We hypothesize that while these parameters are mildly affected by most myosin HCM-causing mutations, a major effect of a majority of myosin HCM mutations is likely to involve an increase in the number of myosin heads that are functionally accessible (Na) for interaction with actin in the sarcomere. We consider a model involving three types of interactions involving the myosin mesa and the converter domain of the myosin motor that hold myosin heads in a sequestered state, likely to be released in a graded manner as the demands on the heart increase: 1) the two myosin heads binding to one another, 2) one head binding to its own coiled-coil tail, and 3) the other head binding to myosin binding protein-C. In addition there is clear evidence of interaction between the coiled-coil tail of myosin and myosin binding protein-C. Experimentally, here we focus on myosin head bin...Continue Reading

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Mentioned in this Paper

Coil Device Component
Sarcomeres
Myosin Head/Neck Binding
Actins
Hypertrophic Cardiomyopathy
Hyperactive Behavior
Myosin Phosphatase Myosin Binding
Contraction (Finding)
Coiled-Coil Domain
Head of myosin

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