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


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 (? and ?), 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.

SUBMITTER: Ellisdon AM 

PROVIDER: S-EPMC4687532 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Ellisdon Andrew M AM   Reboul Cyril F CF   Panjikar Santosh S   Huynh Kitmun K   Oellig Christine A CA   Winter Kelly L KL   Dunstone Michelle A MA   Hodgson Wayne C WC   Seymour Jamie J   Dearden Peter K PK   Tweten Rodney K RK   Whisstock James C JC   McGowan Sheena S  

Proceedings of the National Academy of Sciences of the United States of America 20151201 50


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 (α and β), each of which comprises an N-terminal pore-forming MACPF/CDC domain,  ...[more]

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