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    Structural and functional integration of the PLCγ interaction domains critical for regulatory mechanisms and signaling deregulation

    Bunney, T.D. and Esposito, D. and Mas-Droux, C. and Lamber, E. and Baxendale, R.W. and Martins, M. and Cole, Ambrose R. and Svergun, D.I. and Driscoll, P.C. and Katan, M. (2012) Structural and functional integration of the PLCγ interaction domains critical for regulatory mechanisms and signaling deregulation. Structure 20 (12), pp. 2062-2075. ISSN 0969-2126.

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    Abstract

    Multidomain proteins incorporating interaction domains are central to regulation of cellular processes. The elucidation of structural organization and mechanistic insights into many of these proteins, however, remain challenging due to their inherent flexibility. Here, we describe the organization and function of four interaction domains in PLCγ1 using a combination of structural biology and biochemical approaches. Intramolecular interactions within the regulatory region center on the cSH2 domain, the only domain that also interacts with the PLC-core. In the context of fibroblast growth-factor receptor signaling, the coordinated involvement of nSH2 and cSH2 domains mediates efficient phosphorylation of PLCγ1 resulting in the interruption of an autoinhibitory interface by direct competition and, independently, dissociation of PLCγ1 from the receptor. Further structural insights into the autoinhibitory surfaces provide a framework to interpret gain-of-function mutations in PLCγ isoforms linked to immune disorders and illustrate a distinct mechanism for regulation of PLC activity by common interaction domains.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Depositing User: Administrator
    Date Deposited: 18 Oct 2012 11:39
    Last Modified: 17 Apr 2013 12:25
    URI: http://eprints.bbk.ac.uk/id/eprint/5300

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