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The myosin-activated thin filament regulatory state, M− -open: a link to hypertrophic cardiomyopathy (HCM)

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Abstract

This review proposes a link between the hypertrophic (HCM) and restrictive cardiomyopathies caused by mutations in several sarcomeric thin filament proteins, and the open state of the three-state muscle regulation theory. The three characteristics of various muscle systems reconstituted from HCM mutated proteins (increased Ca2+-sensitivity, increased basal activity in the absence of Ca2+, and decreased cooperativity) can be explained by the contribution of a myosin-induced open state (M−), which elevates the basal activity and competes with the normal Ca2+-activated pathway. A model based on the three-state theory of regulation, shows how a change in the closed/blocked equilibrium caused by a mutation that weakens the binding of troponin I to tropomyosin-actin can produce the characteristics of HCM. This review also shows that in the M− state, Ca2+ can shift the closed–open equilibrium of the N-terminal hydrophobic region of troponin C without affecting activity.

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Acknowledgments

We thank our colleagues, Dr. Zenon Grabarek and Dr. Franklin Fuchs for reading an early draft of the manuscript and providing thoughtful input. We appreciate permission from Drs. Dan Fitzsimons and Richard Moss and by Drs. Tomoyoshi Kobayashi and John Solaro for the use of their published figures. Support by Welcome Trust Program Grant 085309 (to MAG) is also acknowledged.

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  1. 4416 Great Meadow Rd, Dedham, MA, USA

    Sherwin S. Lehrer

  2. School of Biosciences, University of Kent, Canterbury, Kent, UK

    Michael A. Geeves

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  1. Sherwin S. Lehrer
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  2. Michael A. Geeves
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Correspondence to Sherwin S. Lehrer.

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Sherwin S. Lehrer was formerly at Boston Biomedical Research Institute, and Neurology Department, Harvard Medical School.

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Lehrer, S.S., Geeves, M.A. The myosin-activated thin filament regulatory state, M− -open: a link to hypertrophic cardiomyopathy (HCM). J Muscle Res Cell Motil 35, 153–160 (2014). https://doi.org/10.1007/s10974-014-9383-z

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