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Structural basis for Ca2+-mediated interaction of the perforin C2 domain with lipid membranes
Structural highlights
FunctionPERF_MOUSE Plays a key role in secretory granule-dependent cell death, and in defense against virus-infected or neoplastic cells. Can insert into the membrane of target cells in its calcium-bound form, oligomerize and form large pores. Promotes cytolysis and apoptosis of target cells by facilitating the uptake of cytotoxic granzymes.[1] [2] [3] [4] [5] Publication Abstract from PubMedNatural killer (NK) cells and cytotoxic T-lymphocytes (CTL) deploy perforin (Prf) and granzymes to kill infected host cells. Perforin, secreted by immune cells, binds target membranes to form pores that deliver pro-apoptotic granzymes into the target cell. A crucial first step in this process is interaction of its C2 domain with target cell membranes, which is a calcium-dependent event. Some aspects of this process are understood, but many molecular details remain unclear. To address this, we investigated the mechanism of Ca2+ and lipid binding to the C2 domain by NMR spectroscopy and X-ray crystallography. Calcium titrations, together with dodecylphosphocholine (DPC) micelle experiments confirmed that multiple Ca2+ ions bind within the calcium binding regions (CBR), activating perforin with respect to membrane binding. We have also determined the affinities of several of these binding sites and shown that this interaction causes a significant structural rearrangement in CBR1. Thus, it is proposed that Ca2+-binding at the weakest affinity site triggers changes in the C2 domain that facilitate its interaction with lipid membranes. Structural Basis for Ca2+-mediated Interaction of the Perforin C2 Domain with Lipid Membranes.,Yagi H, Conroy PJ, Leung EW, Law RH, Trapani JA, Voskoboinik I, Whisstock JC, Norton RS J Biol Chem. 2015 Aug 25. pii: jbc.M115.668384. PMID:26306037[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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