Stonefish toxin defines an ancient branch of the perforin-like superfamily.
Andrew M EllisdonCyril F ReboulSantosh PanjikarKitmun HuynhChristine A OelligKelly L WinterMichelle A DunstoneWayne C HodgsonJamie SeymourPeter K DeardenRodney K TwetenJames C WhisstockSheena McGowanPublished in: Proceedings of the National Academy of Sciences of the United States of America (2015)
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.
Keyphrases
- cell cycle
- escherichia coli
- high resolution
- electronic health record
- dna damage
- binding protein
- computed tomography
- dna repair
- oxidative stress
- magnetic resonance imaging
- cystic fibrosis
- big data
- gene expression
- protein protein
- single cell
- small molecule
- low density lipoprotein
- drug delivery
- cancer therapy
- deep learning
- staphylococcus aureus
- single molecule
- drug induced
- dna methylation
- contrast enhanced