Stonefish toxin defines an ancient branch of the perforin-like superfamily
Stonefish toxin defines an ancient branch of the perforin-like superfamily
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DOI：
10.1073/pnas.1507622112
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发表时间：
2015-12-15
影响因子：
11.1
通讯作者：
McGowan, Sheena
中科院分区：
文献类型：
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作者：
Ellisdon, Andrew M.;Reboul, Cyril F.;McGowan, Sheena
石鱼毒液中的致命因素是石毒素(SNTX)，它是一种异二聚体细胞溶解蛋白，可导致人类和本地捕食者的心血管衰竭。在这里，利用X射线结晶学，我们得到了意想不到的发现，SNTX是膜攻击复合体-穿孔素/胆固醇依赖细胞溶素(MACPF/CDC)超家族的一个古老分支的成孔成员。SNTX由两个同源亚基(α和β)组成，每个亚基都包括一个N端形成孔的MACPF/CDC结构域、一个中心粘附靶向结构域、一个硫氧还蛋白结构域、以及一个C-末端类似撬动蛋白的三聚体家族SLA和兰尼定受体免疫识别结构域。重要的是，结构表明这两个MACPF结构域相互复杂，并排列成稳定的早期前孔样组装。这些数据为MACPF/CDC蛋白质如何组装成膜表面的前孔提供了长期追求的近原子分辨率洞察。此外，我们的分析表明，SNTX样MACPF/CDCs在真核生物中广泛分布，并在毒液外发挥更广泛的可能与免疫相关的功能。
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.