A Common Fold Mediates Vertebrate Defense and Bacterial Attack

• DOI: 10.1126/science.1144706
• Publication Date: 2007-08-24T01:20:12Z
• Authors: Carlos J. Rosado; Ashley M. Buckle; Ruby H. P. Law; Rebecca E. Butcher; Wan-Ting Kan; Catherina H. Bird; Kheng Ung; Kylie A. Browne; Katherine Baran; Tanya A. Bashtann...; Noel G. Faux; Wilson Wong; Corrine J. Porter; Robert N. Pike; Andrew M. Ellisdon; Mary C. Pearce; Stephen P. Bottomley; Jonas Emsley; A. Ian Smith; Jamie Rossjohn; Elizabeth L. Hart...; Ilia Voskoboinik; Joseph A. Trapani; Phillip I. Bird; Michelle A. Dunstone; James C. Whisstock
• Keywords: Pore Forming Cytotoxic Proteins; 0301 basic medicine; Protein Folding; Membrane Glycoproteins; Cytotoxins; Perforin; Protein Conformation; Amino Acid Motifs; Molecular Sequence Data; Complement Membrane Attack Complex; Crystallography, X-Ray; Protein Structure, Secondary; Protein Structure, Tertiary; 3. Good health; 03 medical and health sciences; Bacterial Proteins; Vertebrates; Animals; Amino Acid Sequence; Photorhabdus

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.