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Science:人体免疫蛋白和细菌毒素起源相同

来源:生物谷 2007-08-28 12:36

澳大利亚科学家发现,一种对于对抗肿瘤、病毒和细菌感染等很重要的人类免疫蛋白属于古老且致命的毒素种类,科学家过去一直认为它们只存在于细菌中。这种被称为穿孔素(perforins)的蛋白和造成炭疽热、猩红热等的细菌毒素类似。得到以上发现的是Monash大学生物医学系的James  Whisstock教授和Michelle  Dunstone博士领导的小组。

Whisstock教授表示当他们确认perforins和细菌毒素有着相同祖先时感到非常震惊。他说:“经过千百万年进化,细菌发展出了这些蛋白作为攻击武器。而动物同时也进化得到类似蛋白防御进攻,这是一场胜负未明的分子竞赛。”

Whisstock表示它们之所以被称为穿孔素,是因为它们通过在细菌、被感染细胞、癌细胞上穿孔来杀死入侵者。Whisstock说:“缺少穿孔素的人会患上严重的血液疾病——嗜血细胞性淋巴组织细胞增生症,并更易患上癌症。同时穿孔素也是很危险的分子,如果得不到控制,将造成免疫系统大破坏。通过了解穿孔素工作机制,就可以在感染性疾病和移植排异反应发生时控制它们。”

利用X射线结晶学,小组得到了穿孔素Plu-MACPF的结构,这种和细菌毒素类似的结构告诉了科学家此类蛋白的工作机制。结果发表在Science上。Dunstone表示这是9年研究结果的积累,她说:“我们最终知道了穿孔素的结构和工作机制,因此可以利用这些知识找到对抗疾病的新方法。”

Whisstock认为特定穿孔素不但帮助人类对抗细菌和病毒入侵,而且对于人类物种传播很重要,因为它们在胚胎植入方面也起作用。他说:“具有讽刺意味的是,造成我们害怕的疾病的毒素和与繁殖有关的蛋白属于同一家族。”

研究小组科学家还来自国家健康和医学研究委员会的蛋白酶系统生物计划、澳大利亚研究委员会微生物基因组结构和功能中心、Peter  MacCallum肿瘤中心等。X射线数据通过芝加哥的高级光子源得到。  

原文链接:http://www.physorg.com/news107097729.html

原始出处:

Published Online August 23, 2007
Science DOI: 10.1126/science.1144706

Submitted on May 7, 2007
Accepted on July 31, 2007

A Common Fold Mediates Vertebrate Defense and Bacterial Attack

Carlos J. Rosado 1, Ashley M. Buckle 2, Ruby H. P. Law 2, Rebecca E. Butcher 3, Wan-Ting Kan 1, Catherina H. Bird 2, Kheng Ung 2, Kylie A. Browne 4, Katherine Baran 4, Tanya A. Bashtannyk-Puhalovich 2, Noel G. Faux 2, Wilson Wong 1, Corrine J. Porter 1, Robert N. Pike 2, Andrew M. Ellisdon 2, Mary C. Pearce 2, Stephen P. Bottomley 2, Jonas Emsley 5, A. Ian Smith 1, Jamie Rossjohn 1, Elizabeth L. Hartland 6, Ilia Voskoboinik 7, Joseph A. Trapani 8, Phillip I. Bird 2, Michelle A. Dunstone 9*, James C. Whisstock 1*

1 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.; ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC, 3800, Australia.
2 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
3 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.; Division of Virology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
4 Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, VIC, 3002, Australia.
5 Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK.
6 Department of Microbiology, Monash University, Clayton, VIC, 3800, Australia.
7 Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, VIC, 3002, Australia.; Department of Genetics, University of Melbourne, Parkville, VIC 3010, Australia.
8 Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, VIC, 3002, Australia.; Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia.
9 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.; Department of Microbiology, Monash University, Clayton, VIC, 3800, Australia.

* To whom correspondence should be addressed.
Michelle A. Dunstone , E-mail: michelle.dunstone@med.monash.edu.au
James C. Whisstock , E-mail: james.whisstock@med.monash.edu.au

These authors contributed equally to this work.

Proteins containing Membrane Attack Complex / Perforin (MACPF) domains play important roles in vertebrate immunity, embryonic development and neural cell migration. In vertebrates, C9 and perforin form oligomeric pores that lyse bacteria and kill virus-infected cells, respectively. However, the mechanism of MACPF function is unknown. We determined the crystal structure of a bacterial MACPF protein, Plu-MACPF from Photorhabdus luminescens, to 2.0 Å resolution. The MACPF domain reveals structural similarity with pore forming cholesterol-dependent cytolysins (CDCs) from Gram positive bacteria. This suggests that lytic MACPF proteins may use a CDC-like mechanism to form pores and disrupt cell membranes. Sequence similarity between bacterial and vertebrate MACPF domains suggest that the fold of the CDCs, a family of proteins important for bacterial pathogenesis, is likely used by vertebrates for defence against infection.

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