澳大利亞科學(xué)家發(fā)現(xiàn)，一種對于對抗腫瘤,、病毒和細菌感染等很重要的人類免疫蛋白屬于古老且致命的毒素種類,，科學(xué)家過去一直認為它們只存在于細菌中,。這種被稱為穿孔素（perforins）的蛋白和造成炭疽熱、猩紅熱等的細菌毒素類似,。得到以上發(fā)現(xiàn)的是Monash大學(xué)生物醫(yī)學(xué)系的James Whisstock教授和Michelle Dunstone博士領(lǐng)導(dǎo)的小組,。
Whisstock教授表示當他們確認perforins和細菌毒素有著相同祖先時感到非常震驚。他說：“經(jīng)過千百萬年進化,，細菌發(fā)展出了這些蛋白作為攻擊武器,。而動物同時也進化得到類似蛋白防御進攻，這是一場勝負未明的分子競賽,。”
Whisstock表示它們之所以被稱為穿孔素,，是因為它們通過在細菌、被感染細胞,、癌細胞上穿孔來殺死入侵者,。Whisstock說：“缺少穿孔素的人會患上嚴重的血液疾病——嗜血細胞性淋巴組織細胞增生癥，并更易患上癌癥,。同時穿孔素也是很危險的分子，如果得不到控制,，將造成免疫系統(tǒng)大破壞,。通過了解穿孔素工作機制，就可以在感染性疾病和移植排異反應(yīng)發(fā)生時控制它們,。”
利用X射線結(jié)晶學(xué),，小組得到了穿孔素Plu－MACPF的結(jié)構(gòu)，這種和細菌毒素類似的結(jié)構(gòu)告訴了科學(xué)家此類蛋白的工作機制,。結(jié)果發(fā)表在Science上,。Dunstone表示這是9年研究結(jié)果的積累，她說：“我們最終知道了穿孔素的結(jié)構(gòu)和工作機制,，因此可以利用這些知識找到對抗疾病的新方法,。”
Whisstock認為特定穿孔素不但幫助人類對抗細菌和病毒入侵，而且對于人類物種傳播很重要,，因為它們在胚胎植入方面也起作用,。他說：“具有諷刺意味的是，造成我們害怕的疾病的毒素和與繁殖有關(guān)的蛋白屬于同一家族,。”
研究小組科學(xué)家還來自國家健康和醫(yī)學(xué)研究委員會的蛋白酶系統(tǒng)生物計劃,、澳大利亞研究委員會微生物基因組結(jié)構(gòu)和功能中心、Peter MacCallum腫瘤中心等,。X射線數(shù)據(jù)通過芝加哥的高級光子源得到,。
原文鏈接：http://www.physorg.com/news107097729.html
原始出處:
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: [email protected]
James C. Whisstock , E-mail: [email protected]
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.
