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

Reports

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

A Common Fold Mediates Vertebrate Defense and Bacterial Attack

Carlos J. Rosado 1{dagger}, Ashley M. Buckle 2{dagger}, Ruby H. P. Law 2{dagger}, 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{at}med.monash.edu.au
James C. Whisstock , E-mail: james.whisstock{at}med.monash.edu.au

{dagger}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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