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J Muscle Res Cell Motil. 2014 Apr;35(2):153-60. doi: 10.1007/s10974-014-9383-z. Epub 2014 Apr 17.

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

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1
, 4416 Great Meadow Rd, Dedham, MA, USA, Sherwin.lehrer@gmail.com.

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.

PMID:
24740688
DOI:
10.1007/s10974-014-9383-z
[Indexed for MEDLINE]

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