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  Functional characterization of the human alpha-cardiac actin mutations Y166C and M305L involved in hypertrophic cardiomyopathy

Müller, M., Mazur, A. J., Behrmann, E., Diensthuber, R. P., Radke, M. B., Qu, Z., et al. (2012). Functional characterization of the human alpha-cardiac actin mutations Y166C and M305L involved in hypertrophic cardiomyopathy. Cellular and molecular life sciences: CMLS, 69(20), 3457-3479. doi:10.1007/s00018-012-1030-5.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-63CC-E Version Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-63CD-C
Genre: Journal Article

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http://www.ncbi.nlm.nih.gov/pubmed/22643837 (Any fulltext)
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http://link.springer.com/article/10.1007%2Fs00018-012-1030-5 (Any fulltext)
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 Creators:
Müller, M., Author
Mazur, A. J., Author
Behrmann, E.1, Author
Diensthuber, R. P., Author
Radke, M. B., Author
Qu, Z., Author
Littwitz, C., Author
Raunser, S., Author
Schoenenberger, C. A., Author
Manstein, D. J., Author
Mannherz, H. G., Author
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1External Organizations, ou_persistent22              

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Free keywords: Actin Cytoskeleton/*metabolism Actins/*genetics/*metabolism Adenoviridae/genetics Animals Animals, Newborn Baculoviridae/genetics Binding Sites Cardiomyopathy, Hypertrophic/genetics/*metabolism Cells, Cultured Humans Immunoblotting Mutation/*genetics Myocytes, Cardiac/cytology/metabolism Myosins/metabolism Rats Sarcomeres/physiology
 Abstract: Inherited cardiomyopathies are caused by point mutations in sarcomeric gene products, including alpha-cardiac muscle actin (ACTC1). We examined the biochemical and cell biological properties of the alpha-cardiac actin mutations Y166C and M305L identified in hypertrophic cardiomyopathy (HCM). Untagged wild-type (WT) cardiac actin, and the Y166C and M305L mutants were expressed by the baculovirus/Sf9-cell system and affinity purified by immobilized gelsolin G4-6. Their correct folding was verified by a number of assays. The mutant actins also displayed a disturbed intrinsic ATPase activity and an altered polymerization behavior in the presence of tropomyosin, gelsolin, and Arp2/3 complex. Both mutants stimulated the cardiac beta-myosin ATPase to only 50 % of WT cardiac F-actin. Copolymers of WT and increasing amounts of the mutant actins led to a reduced stimulation of the myosin ATPase. Transfection of established cell lines revealed incorporation of EGFP- and hemagglutinin (HA)-tagged WT and both mutant actins into cytoplasmic stress fibers. Adenoviral vectors of HA-tagged WT and Y166C actin were successfully used to infect adult and neonatal rat cardiomyocytes (NRCs). The expressed HA-tagged actins were incorporated into the minus-ends of NRC thin filaments, demonstrating the ability to form hybrid thin filaments with endogenous actin. In NRCs, the Y166C mutant led after 72 h to a shortening of the sarcomere length when compared to NRCs infected with WT actin. Thus our data demonstrate that a mutant actin can be integrated into cardiomyocyte thin filaments and by its reduced mode of myosin interaction might be the basis for the initiation of HCM.

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 Dates: 2012
 Publication Status: Issued
 Pages: -
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 Rev. Type: -
 Identifiers: Other: 22643837
DOI: 10.1007/s00018-012-1030-5
ISSN: 1420-9071 (Electronic)
ISSN: 1420-682X (Linking)
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Title: Cellular and molecular life sciences : CMLS
  Alternative Title : Cell. Mol. Life Sci.
Source Genre: Journal
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Pages: - Volume / Issue: 69 (20) Sequence Number: - Start / End Page: 3457 - 3479 Identifier: -