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Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation

DOI: 10.1042/BCJ20160421 DOI Help

Authors: N. J. Haywood (University of Leeds) , M. Wolny (University of Leeds) , B. Rogers (University of Leeds) , Chi Hung Trinh (Institute of Molecular and Cellular Biology, University of Leeds) , Y. Shuping (University of Leeds) , T. A. Edwards (University of Leeds) , M. Peckham (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal , VOL 473 , PAGES 2485 - 2493

State: Published (Approved)
Published: August 2016
Diamond Proposal Number(s): 6386

Abstract: α-actinin 2 (ACTN2) is the only muscle isoform of α-actinin expressed in cardiac muscle. Mutations in this protein have been implicated in mild to moderate forms of hypertrophic cardiomyopathy (HCM). We have investigated the effects of two mutations identified from HCM patients; A119T and G111V, on the secondary and tertiary structure of a purified actin binding domain of ACTN2 by circular dichroism and X-ray crystallography, and show small but distinct changes for both mutations. We also find that both mutants have reduced F-actin binding affinity, although the differences are not significant. The full length mEos2 tagged protein expressed in adult cardiomyocytes shows that both mutations additionally affect Z-disc localisation and dynamic behaviour. Overall, these two mutations have small effects on structure, function and behaviour, which may contribute to a mild phenotype for this disease.

Journal Keywords: actin α-actinin cardiomyocytes crystal structure familial hypertrophic cardiomyopathy imaging

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 15/08/2016 11:24

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