Structural Basis for Ca2+-mediated Interaction of the Perforin C2 Domain with Lipid Membranes

摘要: Natural killer cells and cytotoxic T-lymphocytes deploy perforin granzymes to kill infected host cells. Perforin, secreted by immune cells, binds target membranes form pores that deliver pro-apoptotic into the cell. A crucial first step in this process is interaction of its C2 domain with cell membranes, which a calcium-dependent event. Some aspects are understood, but many molecular details remain unclear. To address this, we investigated mechanism Ca(2+) lipid binding NMR spectroscopy x-ray crystallography. Calcium titrations, together dodecylphosphocholine micelle experiments, confirmed multiple ions bind within calcium-binding regions, activating respect membrane binding. We have also determined affinities several these sites shown causes significant structural rearrangement CBR1. Thus, it proposed at weakest affinity site triggers changes facilitate membranes.