Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1862, Issue 8, Pages 1453-1458Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2016.04.013
Keywords
Myopathy; Actin; Contractile dysfunction; Small-angle X-ray scattering; In vitro motility assay; Molecular dynamics
Funding
- Medical Research Council UK [MR/N002768/1]
- National Natural Science Foundation of China [21403182]
- Council of Hong Kong [CityU 21300014]
- Office of Science of the U.S. Department of Energy [DE-AC05-00OR22725]
- British Heart Foundation [RG/11/20/29266] Funding Source: researchfish
- Medical Research Council [MR/N002768/1] Funding Source: researchfish
- MRC [MR/N002768/1] Funding Source: UKRI
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In humans, more than 200 missense mutations have been identified in the ACTA1 gene. The exact molecular mechanisms by which, these particular mutations become toxic and lead to muscle weakness and myopathies remain obscure. To address this, here, we performed a molecular dynamics simulation, and we used a broad range of biophysical assays to determine how the lethal and myopathy-related H40Y amino acid substitution in actin affects the structure, stability, and function of this protein. Interestingly, our results showed that H40Y severely disrupts the DNase I-binding-loop structure and actin filaments. In addition, we observed that normal and mutant actin monomers are likely to form distinctive homopolymers, with mutant filaments being very stiff, and not supporting proper myosin binding. These phenomena underlie the toxicity of H40Y and may be considered as important triggering factors for the contractile dysfunction, muscle weakness and disease phenotype seen in patients. (C) 2016 The Authors. Published by Elsevier B.V.
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