期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：50
页码：15360-15365
DOI：10.1073/pnas.1507622112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceHere, we present the structure of the pore-forming toxin stonustoxin (SNTX), the lethal factor present in stonefish venom. Our work shows that SNTX comprises two homologous subunits ( and {beta}), each of which belongs to the perforin superfamily of pore-forming immune effectors. In SNTX, the - and {beta}-Membrane Attack Complex-Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) domains interact and form a prepore-like complex. These data provide, to our knowledge, the first high-resolution insights into how MACPF/CDCs interact with one another during pore formation. 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 {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.
