Oral Presentation The 3rd Prato Conference on Pore Forming Proteins 2015

Stonefish toxin defines an extensive new branch of the perforin-like protein superfamily (#13)

Andrew Ellisdon 1 , Cyril Reboul 1 , Santosh Panjikar 2 , Michelle Dunstone 1 , Jamie Seymour 3 , Peter Dearden 4 , Rodney Tweten 5 , James Whisstock 1 , Sheena McGowan 1
  1. Monash University, Clayton, VIC, Australia
  2. Australian Synchrotron, Melbourne, VIC, Australia
  3. Centre for Biodiscovery & Molecular Development of Therapeutics, James Cook University, Cairns, QLD, Australia
  4. Biochemistry, University of Otago, Dunedin, New Zealend
  5. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

The lethal factor in stonefish venom is Stonustoxin (SNTX), a cytolytic protein that induces profound hypotension and cardiovascular collapse in mammals. Here, we make the unexpected finding that SNTX is a pore forming member of a hitherto undiscovered third branch of the Cholesterol Dependent Cytolysin / Membrane Attack Complex/Perforin (CDC/MACPF)-superfamily. Our data suggest that initial SNTX interaction with target membranes is mediated by two C-terminal PRYSPRY domains that are most closely related to the lipid and protein binding PRYSPRY domains of Tripartite motif (TRIM) immune proteins. Two N-terminal CDC/MACPF domains are arranged in a pre-pore like assembly; these data provide unique, and broad, high-resolution insight into how SNTX and other CDC/MACPF proteins assemble into pores. Finally, our analysis reveals that SNTX-like CDCs are distributed throughout eukaryotic life, and likely play a broader, and possibly immune-related function outside venom.