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. 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.
Department of Physics and Materials Science, City University of Hong Kong, Hong Kong.
Chun
C
Chan
Department of Physics and Materials Science, City University of Hong Kong, Hong Kong; City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
Jun
J
Fan
National Heart and Lung Institute, Imperial College London, London, UK.
Andrew E
AE
Messer
National Heart and Lung Institute, Imperial College London, London, UK.
Steve B
SB
Marston
Japan Synchrotron Radiation Research Institute, SPring8, Hyogo, Japan.
Hiroyuki
H
Iwamoto
Centre of Human and Aerospace Physiological Sciences, King's College London, London, UK. Electronic address: julien.ochala@kcl.ac.uk.
Julien
J
Ochala
D000199:Actins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D056004:Molecular Dynamics Simulation; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D017433:Protein Structure, Secondary; D022502:Stress Fibers / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
C000626519:ACTA1 protein, human; D000199:Actins
Actin; Contractile dysfunction; In vitro motility assay; Molecular dynamics; Myopathy; Small-angle X-ray scattering