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Title: Myopathy-inducing mutation H40Y in ACTA1 hampers actin filament structure and function

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. Lastly, 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.
Authors:
 [1] ;  [2] ;  [3] ;  [3] ;  [4] ;  [5]
  1. City Univ. of Hong Kong (Hong Kong)
  2. City Univ. of Hong Kong (Hong Kong); City Univ. of Hong Kong Shenzhen Research Institute, Shenzhen (China)
  3. Imperial College London, London (United Kingdom)
  4. Japan Synchrotron Radiation Research Institute, Hyogo (Japan)
  5. King's College London, London (United Kingdom)
Publication Date:
Grant/Contract Number:
AC05-00OR22725
Type:
Published Article
Journal Name:
Biochimica et Biophysica Acta. Molecular Basis of Disease
Additional Journal Information:
Journal Volume: 1862; Journal Issue: 8; Journal ID: ISSN 0925-4439
Publisher:
Elsevier
Research Org:
King's College London (United Kingdom)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; myopathy; actin; contractile dysfunction; small-angle X-ray scattering; in vitro motility assay; molecular dynamics
OSTI Identifier:
1324482
Alternate Identifier(s):
OSTI ID: 1343925