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    The molecular basis for perforin oligomerization and transmembrane pore assembly

    Baran, K. and Dunstone, M.A. and Chia, J. and Ciccone, A. and Browne, K.A. and Clarke, C.J.P. and Lukoyanova, Natalya and Saibil, Helen R. and Whisstock, J.C. and Voskoboinik, I. and Trapani, J.A. (2009) The molecular basis for perforin oligomerization and transmembrane pore assembly. Immunity 30 (5), pp. 684-695. ISSN 1074-7613.

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    Abstract

    Perforin, a pore-forming protein secreted by cytotoxic lymphocytes, is indispensable for destroying virus-infected cells and for maintaining immune homeostasis. Perforin polymerizes into transmembrane channels that inflict osmotic stress and facilitate target cell uptake of proapoptotic granzymes. Despite this, the mechanism through which perforin monomers self-associate remains unknown. Our current study establishes the molecular basis for perforin oligomerization and pore assembly. We show that after calcium-dependent membrane binding, direct ionic attraction between the opposite faces of adjacent perforin monomers was necessary for pore formation. By using mutagenesis, we identified the opposing charges on residues Arg213 (positive) and Glu343 (negative) to be critical for intermolecular interaction. Specifically, disrupting this interaction had no effect on perforin synthesis, folding, or trafficking in the killer cell, but caused a marked kinetic defect of oligomerization at the target cell membrane, severely disrupting lysis and granzyme B-induced apoptosis. Our study provides important insights into perforin's mechanism of action.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 04 Aug 2010 14:09
    Last Modified: 06 Dec 2016 11:14
    URI: http://eprints.bbk.ac.uk/id/eprint/1082

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