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Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation.

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  • معلومة اضافية
    • المصدر:
      Publisher: Published by Portland Press on behalf of the Biochemical Society Country of Publication: England NLM ID: 2984726R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1470-8728 (Electronic) Linking ISSN: 02646021 NLM ISO Abbreviation: Biochem J Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: London, UK : Published by Portland Press on behalf of the Biochemical Society
    • الموضوع:
      Mutation*; Actinin/*metabolism ; Actins/*metabolism ; Calcium-Binding Proteins/*metabolism ; Cardiomyopathy, Hypertrophic/*metabolism ; Microfilament Proteins/*metabolism ; Myocytes, Cardiac/*metabolism; Actinin/chemistry ; Actinin/genetics ; Adult ; Cardiomyopathy, Hypertrophic/genetics ; Circular Dichroism ; Crystallography, X-Ray ; Humans ; Protein Binding ; Protein Structure, Secondary ; Calponins
    • نبذة مختصرة :
      α-Actinin-2 (ACTN2) is the only muscle isoform of α-actinin expressed in cardiac muscle. Mutations in this protein have been implicated in mild to moderate forms of hypertrophic cardiomyopathy (HCM). We have investigated the effects of two mutations identified from HCM patients, A119T and G111V, on the secondary and tertiary structure of a purified actin binding domain (ABD) of ACTN2 by circular dichroism and X-ray crystallography, and show small but distinct changes for both mutations. We also find that both mutants have reduced F-actin binding affinity, although the differences are not significant. The full length mEos2 tagged protein expressed in adult cardiomyocytes shows that both mutations additionally affect Z-disc localization and dynamic behaviour. Overall, these two mutations have small effects on structure, function and behaviour, which may contribute to a mild phenotype for this disease.
      (© 2016 The Author(s).)
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    • Grant Information:
      BB/I007423/1 United Kingdom Biotechnology and Biological Sciences Research Council; WT094232 United Kingdom Wellcome Trust; BB/J014443/1 United Kingdom Biotechnology and Biological Sciences Research Council
    • Contributed Indexing:
      Keywords: actin; cardiomyocytes; crystal structure; familial hypertrophic cardiomyopathy; imaging; α-actinin
    • الرقم المعرف:
      0 (ACTN2 protein, human)
      0 (Actins)
      0 (Calcium-Binding Proteins)
      0 (Microfilament Proteins)
      11003-00-2 (Actinin)
    • الموضوع:
      Date Created: 20160612 Date Completed: 20170606 Latest Revision: 20240529
    • الموضوع:
      20240529
    • الرقم المعرف:
      PMC4980809
    • الرقم المعرف:
      10.1042/BCJ20160421
    • الرقم المعرف:
      27287556