4WVM

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

(2015) Proc Natl Acad Sci U S A 112: 15360-15365

• PubMed: 26627714 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1073/pnas.1507622112
• Primary Citation of Related Structures:  
  4WVM


• PubMed 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 (α and β), 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.

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Organizational Affiliation: 

Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, 3800, Australia;