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

Chun Chan, Jun Fan, Andrew E. Messer, Steve B. Marston, Hiroyuki Iwamoto, Julien Ochala*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1453-1458
Number of pages6
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number8
Publication statusPublished - 1 Aug 2016
Externally publishedYes


  • Actin
  • Contractile dysfunction
  • In vitro motility assay
  • Molecular dynamics
  • Myopathy
  • Small-angle X-ray scattering


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