Stonefish toxin defines an ancient branch of the perforin-like superfamily

Andrew M Ellisdon, Cyril F Reboul, Santosh Panjikar, Kitmun Huynh, Christine A Oellig, Kelly L Winter, Michelle A Dunstone, Wayne C Hodgson, Jamie E Seymour, Peter K Dearden, Rodney K Tweten, James C Whisstock, Sheena McGowan

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

The lethal factor in stonefish venom is stonustoxin (SNTX), a heterodimeric cytolytic protein that induces cardiovascular collapse in humans and native predators. Here, using X-ray crystallography, we make the unexpected finding that SNTX is a pore-forming member of an ancient branch of the Membrane Attack Complex-Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily. SNTX comprises two homologous subunits (alpha and beta), each of which comprises an N-terminal pore-forming MACPF/CDC domain, a central focal adhesion-targeting domain, a thioredoxin domain, and a C-terminal tripartite motif family-like PRY SPla and the RYanodine Receptor immune recognition domain. Crucially, the structure reveals that the two MACPF domains are in complex with one another and arranged into a stable early prepore-like assembly. These data provide long sought after near-atomic resolution insights into how MACPF/CDC proteins assemble into prepores on the surface of membranes. Furthermore, our analyses reveal that SNTX-like MACPF/CDCs are distributed throughout eukaryotic life and play a broader, possibly immune-related function outside venom.
Original languageEnglish
Pages (from-to)15360 - 15365
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number50
DOIs
Publication statusPublished - 2015

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