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  • Title: The myosin-activated thin filament regulatory state, M⁻-open: a link to hypertrophic cardiomyopathy (HCM).
    Author: Lehrer SS, Geeves MA.
    Journal: J Muscle Res Cell Motil; 2014 Apr; 35(2):153-60. PubMed ID: 24740688.
    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 Ca(2+)-sensitivity, increased basal activity in the absence of Ca(2+), 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 Ca(2+)-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, Ca(2+) can shift the closed-open equilibrium of the N-terminal hydrophobic region of troponin C without affecting activity.
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