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.
- Research Organization:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); King's College, London (United Kingdom)
- Sponsoring Organization:
- USDOE Office of Science (SC)
- Grant/Contract Number:
- AC05-00OR22725
- OSTI ID:
- 1324482
- Alternate ID(s):
- OSTI ID: 1343925
- Journal Information:
- Biochimica et Biophysica Acta. Molecular Basis of Disease, Journal Name: Biochimica et Biophysica Acta. Molecular Basis of Disease Vol. 1862 Journal Issue: 8; ISSN 0925-4439
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- Netherlands
- Language:
- English
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