ArticleProceedings of the National Academy of Sciences of the United States of America2015
Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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45 citing papers in PubMed, 62 citations in OpenAlex.
- Genetic and molecular mechanisms of hereditary thoracic aortic aneurysm and dissection (Review).Molecular medicine reports · 2026Review
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- Dynamical features of smooth muscle actin pathological mutants: The arginine-257(258)-Cysteine cases.Computational and structural biotechnology journal · 2025Article
- Biochemical characterization of cardiac α-actin mutations A21V and D26N implicated in hypertrophic cardiomyopathy.Cytoskeleton (Hoboken, N.J.) · 2024Article
- Dilated cardiomyopathy-associated skeletal muscle actin (ACTA1) mutation R256H disrupts actin structure and function and causes cardiomyocyte hypocontractility.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A yeast based assay establishes the pathogenicity of novel missense ACTA2 variants associated with aortic aneurysms.European journal of human genetics : EJHG · 2024Article
- Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections.Basic research in cardiology · 2024Review
- Molecular mechanisms linking missense ACTG2 mutations to visceral myopathy.Science advances · 2024Article
- Article
- Purification of modified mammalian actin isoforms for in vitro reconstitution assays.European journal of cell biology · 2023Review
- Purification of human β- and γ-actin from budding yeast.Journal of cell science · 2023Article
- Acetylation of fission yeast tropomyosin does not promote differential association with cognate formins.Cytoskeleton (Hoboken, N.J.) · 2023Article
- Molecular and Cellular Mechanisms Involved in Aortic Wall Aneurysm Development.Diagnostics (Basel, Switzerland) · 2023Review
- A solution to the long-standing problem of actin expression and purification.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome.American journal of medical genetics. Part A · 2022Article
- Tracking an Elusive Killer: State of the Art of Molecular-Genetic Knowledge and Laboratory Role in Diagnosis and Risk Stratification of Thoracic Aortic Aneurysm and Dissection.Diagnostics (Basel, Switzerland) · 2022Review
- The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections.European journal of clinical investigation · 2022Review
- Molecular phenotyping and functional assessment of smooth muscle-like cells with pathogenic variants in aneurysm genes ACTA2, MYH11, SMAD3 and FBN1.Human molecular genetics · 2021Article
- The actomyosin interface contains an evolutionary conserved core and an ancillary interface involved in specificity.Nature communications · 2021Article
- Review
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5 authors at 1 institution in 1 country.
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Abstract
Point mutations in vascular smooth muscle α-actin (SM α-actin), encoded by the gene ACTA2, are the most prevalent cause of familial thoracic aortic aneurysms and dissections (TAAD). Here, we provide the first molecular characterization, to our knowledge, of the effect of the R258C mutation in SM α-actin, expressed with the baculovirus system. Smooth muscles are unique in that force generation requires both interaction of stable actin filaments with myosin and polymerization of actin in the subcortical region. Both aspects of R258C function therefore need investigation. Total internal reflection fluorescence (TIRF) microscopy was used to quantify the growth of single actin filaments as a function of time. R258C filaments are less stable than WT and more susceptible to severing by cofilin. Smooth muscle tropomyosin offers little protection from cofilin cleavage, unlike its effect on WT actin. Unexpectedly, profilin binds tighter to the R258C monomer, which will increase the pool of globular actin (G-actin). In an in vitro motility assay, smooth muscle myosin moves R258C filaments more slowly than WT, and the slowing is exacerbated by smooth muscle tropomyosin. Under loaded conditions, small ensembles of myosin are unable to produce force on R258C actin-tropomyosin filaments, suggesting that tropomyosin occupies an inhibitory position on actin. Many of the observed defects cannot be explained by a direct interaction with the mutated residue, and thus the mutation allosterically affects multiple regions of the monomer. Our results align with the hypothesis that defective contractile function contributes to the pathogenesis of TAAD.
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