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The structural basis for membrane binding and pore formation by lymphocyte perform

机译：膜结合和淋巴细胞形成孔的结构基础

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摘要

Natural killer cells and cytotoxic T lymphocytes accomplish the critically important function of killing virus-infected and neo-plastic cells. They do this by releasing the pore-forming protein perform and granzyme proteases from cytoplasmic granules into the cleft formed between the abutting killer and target cell membranes. Perform, a 67-kilodalton multidomain protein, oligo-merizes to form pores that deliver the pro-apoptopic granzymes into the cytosol of the target cell. The importance of perform is highlighted by the fatal consequences of congenital perform deficiency, with more than 50 different perforin mutations linked to familial haemophagocytic lymphohistiocytosis (type 2 FHL). Here we elucidate the mechanism of perforin pore formation by determining the X-ray crystal structure of monomeric murine perforin, together with a cryo-electron microscopy reconstruction of the entire perforin pore. Perforin is a thin 'key-shaped' molecule, comprising an amino-terminal membrane attack complex perforin-like (MACPF)/cholesterol dependent cytolysin (CDC) domain followed by an epidermal growth factor (EGF) domain that, together with the extreme carboxy-terminal sequence, forms a central shelf-like structure. A C-terminal C2 domain mediates initial, Ca~(2+)-dependent membrane binding. Most unexpectedly, however, electron microscopy reveals that the orientation of the perforin MACPF domain in the pore is inside-out relative to the subunit arrangement in CDCs. These data reveal remarkable flexibility in the mechanism of action of the conserved MACPF/CDC fold and provide new insights into how related immune defence molecules such as complement proteins assemble into pores.
机译：天然杀伤细胞和细胞毒性T淋巴细胞具有杀灭病毒感染和赘生性细胞的至关重要的功能。他们通过将形成孔的蛋白质和颗粒酶从细胞质颗粒释放到邻接的杀手和靶细胞膜之间形成的裂缝中来实现。 Perform是一种67千多尔顿的多结构域蛋白，寡聚形成孔，将促凋亡前的颗粒酶递送到靶细胞的细胞质中。先天性表演不足的致命后果突出了表演的重要性，与家族性吞噬细胞性淋巴组织细胞增生症（2型FHL）相关的穿孔素突变超过50种。在这里，我们通过确定单体鼠穿孔素的X射线晶体结构，以及整个穿孔素孔的冷冻电子显微镜重建，来阐明穿孔素孔形成的机理。穿孔素是一种薄的“钥匙形”分子，包含一个氨基末端膜攻击复合物穿孔素样（MACPF）/胆固醇依赖性细胞溶素（CDC）结构域，其后是一个表皮生长因子（EGF）结构域，该结构域与极端羧基-末端序列，形成中央架子状结构。 C端C2结构域介导初始的Ca〜（2+）依赖性膜结合。然而，最出乎意料的是，电子显微镜显示，相对于CDC中的亚基排列，孔中穿孔素MACPF结构域的方向是内而外的。这些数据揭示了保守的MACPF / CDC折叠作用机理的显着灵活性，并为相关免疫防御分子（例如补体蛋白）如何组装成孔提供了新见解。

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  • 来源
    《Nature》 |2010年第7322期|p.447-451|共5页
  • 作者

    Ruby H. P. Law; Natalya Lukoyanova; Ilia Voskoboinik; Tom T. Caradoc-Davies; Katherine Baran; Michelle A. Dunstone; Michael E. DAngelo; Elena V. Orlova; Fasseli Coulibaly; Sandra Verschoor; Kylie A. Browne; Annette Ciccone; Michael J. Kuiper; Phillip I. Bird; Joseph A. Trapani; Helen R. Saibil; James C. Whisstock;

  • 作者单位

    Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria 3800, Australia The ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Melbourne, Victoria 3800, Australia;

    rnCrystallography, Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, UK;

    rnCancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew's Place, East Mel bourne, Victoria 3002, Australia Department of Genetics, The University of Melbourne, Parkville, Victoria 3010, Australia;

    rnAustralian Synchrotron,800 Blackburn Road,Clayton, Mel bourne, Victoria 3168, Australia;

    rnCancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew's Place, East Mel bourne, Victoria 3002, Australia;

    rnDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria 3800, Australia Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia;

    rnDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria 3800, Australia;

    rnCrystallography, Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, UK;

    rnDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria 3800, Australia;

    rnCancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew's Place, East Mel bourne, Victoria 3002, Australia;

    rnCancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew's Place, East Mel bourne, Victoria 3002, Australia;

    rnCancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew's Place, East Mel bourne, Victoria 3002, Australia;

    rnLife Sciences Department, Victorian Partnership of Advanced Computing, Carlton South, Victoria 3053, Australia;

    rnDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria 3800, Australia;

    rnCancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew's Place, East Mel bourne, Victoria 3002, Australia Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia;

    rnCrystallography, Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, UK;

    rnDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria 3800, Australia The ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Melbourne, Victoria 3800, Australia;

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