The Molecular Basis for Perforin Oligomerization and Transmembrane Pore Assembly

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