The study provides structural insights into how Gly-680 mutations in the reactive thiol region of myosin interfere with its motor function by uncoupling structural elements and reducing dynamic properties.
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Hypothesis-generating for myosin-related cardiomyopathy; leaves open translation from animal models to human disease.
The cold-sensitive single-residue mutation of glycine 680 in the reactive thiol region of Dictyostelium discoideum myosin-2 or the corresponding conserved glycine in other myosin isoforms has been reported to interfere with motor function. Here we present the x-ray structures of myosin motor domain mutants G680A in the absence and presence of nucleotide as well as the apo structure of mutant G680V. Our results show that the Gly-680 mutations lead to uncoupling of the reactive thiol region from the surrounding structural elements. Structural and functional data indicate that the mutations induce the preferential population of a state that resembles the ADP-bound state. Moreover, the Gly-680 mutants display greatly reduced dynamic properties, which appear to be related to the recovery of myosin motor function at elevated temperatures.
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Preller et al. (2011) studied this question.
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