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    A structural and functional dissection of the cardiac stress response factor MS1

    Fogl, C. and Puckey, Loretto and Hinssen, U. and Zaleska, M. and el-Mezgueldi, M. and Croasdale, R. and Bowman, A. and Matsukawa, A. and Samani, N.J. and Savva, Renos and Pfuhl, M. (2012) A structural and functional dissection of the cardiac stress response factor MS1. Proteins: Structure, Function, and Bioinformatics 80 (2), pp. 398-409. ISSN 0887-3585.

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    MS1 is a protein predominantly expressed in cardiac and skeletal muscle that is upregulated in response to stress and contributes to development of hypertrophy. In the aortic banding model of left ventricular hypertrophy, its cardiac expression was significantly upregulated within 1 h. Its function is postulated to depend on its F-actin binding ability, located to the C-terminal half of the protein, which promotes stabilization of F-actin in the cell thus releasing myocardin-related transcription factors to the nucleus where they stimulate transcription in cooperation with serum response factor. Initial attempts to purify the protein only resulted in heavily degraded samples that showed distinct bands on SDS gels, suggesting the presence of stable domains. Using a combination of combinatorial domain hunting and sequence analysis, a set of potential domains was identified. The C-terminal half of the protein actually contains two independent F-actin binding domains. The most C-terminal fragment (294–375), named actin binding domain 2 (ABD2), is independently folded while a proximal fragment called ABD1 (193–296) binds to F-actin with higher affinity than ABD2 (KD 2.21 ± 0.47 μM vs. 10.61 ± 0.7 μM), but is not structured by itself in solution. NMR interaction experiments show that it binds and folds in a cooperative manner to F-actin, justifying the label of domain. The architecture of the MS1 C-terminus suggests that ABD1 alone could completely fulfill the F-actin binding function opening up the intriguing possibility that ABD2, despite its high level of conservation, could have developed other functions.


    Item Type: Article
    Keyword(s) / Subject(s): domains, modules, actin binding, combinatorial domain hunting, muscle
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Innovation Management Research, Birkbeck Centre for, Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 19 Dec 2012 16:55
    Last Modified: 02 Aug 2023 17:00


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