A Common Fold Mediates Vertebrate Defense and Bacterial Attack
Carlos J. Rosado,1,2*
Ashley M. Buckle,1*
Ruby H. P. Law,1*
Rebecca E. Butcher,1,3
Wan-Ting Kan,1,2
Catherina H. Bird,1
Kheng Ung,1
Kylie A. Browne,4
Katherine Baran,4
Tanya A. Bashtannyk-Puhalovich,1
Noel G. Faux,1
Wilson Wong,1,2
Corrine J. Porter,1,2
Robert N. Pike,1
Andrew M. Ellisdon,1
Mary C. Pearce,1
Stephen P. Bottomley,1
Jonas Emsley,5
A. Ian Smith,1,2
Jamie Rossjohn,1,2
Elizabeth L. Hartland,6
Ilia Voskoboinik,4,7
Joseph A. Trapani,4,8
Phillip I. Bird,1
Michelle A. Dunstone,1,6
James C. Whisstock1,2
Proteins containing membrane attack complex/perforin (MACPF) domains play important roles in vertebrate immunity, embryonic development, and neural-cell migration. In vertebrates, the ninth component of complement 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 angstrom resolution. The MACPF domain reveals structural similarity with poreforming 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 suggests that the fold of the CDCs, a family of proteins important for bacterial pathogenesis, is probably used by vertebrates for defense against infection.
1 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
2 Australian Research Council (ARC) Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC 3800, Australia.
3 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 Department of Genetics, University of Melbourne, Parkville, VIC 3010, Australia.
8 Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: michelle.dunstone{at}med.monash.edu.au (M.A.D.); james.whisstock{at}med.monash.edu.au (J.C.W.)
