穿孔素
颗粒酶
跨膜蛋白
生物
细胞生物学
溶细胞素
细胞溶解
生物物理学
细胞毒性T细胞
生物化学
受体
毒力
基因
体外
作者
Katherine Baran,Michelle Anne Dunstone,Jenny Chia,Annette Ciccone,Kylie A. Browne,Christopher J. Clarke,Natalya Lukoyanova,Helen R. Saibil,James C. Whisstock,Ilia Voskoboinik,Joseph A. Trapani
出处
期刊:Immunity
[Elsevier]
日期:2009-05-01
卷期号:30 (5): 684-695
被引量:121
标识
DOI:10.1016/j.immuni.2009.03.016
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI