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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Crystal structure of a Trypanosoma brucei metacaspase
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Crystal structure of a Trypanosoma brucei metacaspase

机译：锥虫锥虫半胱天冬酶的晶体结构

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摘要

Metacaspases are distantly related caspase-family cysteine pepti-dases implicated in programmed cell death in plants and lower eukaryotes. They differ significantly from caspases because they are calcium-activated, arginine-specific peptidases that do not require processing or dimerization for activity. To elucidate the basis of these differences and to determine the impact they might have on the control of cell death pathways in lower eukaryotes, the previously undescribed crystal structure of a metacaspase, an inactive mutant of metacaspase 2 (MCA2) from Trypanosoma brucei, has been determined to a resolution of 1.4 A. The structure comprises a core caspase fold, but with an unusual eight-stranded p-sheet that stabilizes the protein as a monomer. Essential aspartic acid residues, in the predicted S1 binding pocket delineate the arginine-specific substrate specificity. In addition, MCA2 possesses an unusual N terminus, which encircles the protein and traverses the catalytic dyad, with Y31 acting as a gatekeeper residue. The calcium-binding site is defined by samarium coordinated by four aspartic acid residues, whereas calcium binding itself induces an allosteric conformational change that could stabilize the active site in a fashion analogous to subunit processing in caspases. Collectively, these data give insights into the mechanistic basis of substrate specificity and mode of activation of MCA2 and provide a detailed framework for understanding the role of metacaspases in cell death pathways of lower eukaryotes.
机译：元蛋白酶是与植物和低等真核生物中程序性细胞死亡有关的远相关的半胱天冬酶家族半胱氨酸肽酶。它们与胱天蛋白酶明显不同，因为它们是钙激活的精氨酸特异性肽酶，不需要进行加工或二聚化即可获得活性。为了阐明这些差异的基础，并确定它们可能对控制低等真核生物中细胞死亡途径的影响，已经提出了以前未描述的metaspaspase的晶体结构，metaspaspase 2的无活性突变体（来自Trypanosoma brucei）经测定，其分辨率为1.4A。该结构包含一个核心caspase折叠，但具有不寻常的八链p-折叠层，可稳定蛋白质作为单体。在预测的S1结合口袋中，必需的天冬氨酸残基描述了精氨酸特异性底物的特异性。此外，MCA2拥有一个不寻常的N末端，该末端环绕着蛋白质并横穿催化二倍体，而Y31则充当看门者残基。钙结合位点由sa与四个天冬氨酸残基配合而定义，而钙结合本身会诱导变构构象变化，该构象变化可能以类似于胱天蛋白酶中亚基加工的方式稳定活性位点。总的来说，这些数据提供了对底物特异性和MCA2激活机制的机械基础的见解，并提供了一个详细的框架，以了解元蛋白酶在低等真核生物的细胞死亡途径中的作用。

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    Karen McLuskey; Jana Rudolf; William R. Proto; Neil W. Isaacs; Graham H. Coombs; Catherine X. Moss; Jeremy C. Mottram;

  • 作者单位

    Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences,University of Glasgow, Glasgow G12 8TA, United Kingdom;

    Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences,University of Glasgow, Glasgow G12 8TA, United Kingdom;

    Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences,University of Glasgow, Glasgow G12 8TA, United Kingdom;

    School of Chemistry, College of Science and Engineering, University of Glasgow, Glasgow G12 8QQ, United Kingdom;

    Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 ORE, United Kingdom;

    Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences,University of Glasgow, Glasgow G12 8TA, United Kingdom;

    Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences,University of Glasgow, Glasgow G12 8TA, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    apoptosis; clan CD; parasite; X-ray crystallography;

    机译：细胞凋亡氏族CD;寄生虫X射线晶体学;

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