Efficient oxidative folding of conotoxins and the radiation of venomous cone snails
Efficient oxidative folding of conotoxins and the radiation of venomous cone snails
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DOI：
10.1073/pnas.2335845100
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发表时间：
2003-11-25
影响因子：
11.1
通讯作者：
Olivera, BM
中科院分区：
文献类型：
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作者：
Bulaj, G;Buczek, O;Olivera, BM
500种不同种类的有毒圆锥蜗牛（Conus属）使用小的，高度结构化的肽（conotoxins）与猎物，捕食者和竞争对手相互作用。这些肽是通过翻译仅属于少数基因超家族的许多基因的mRNA而产生的。每个翻译产物经过加工，产生多种不同的成熟毒素肽（约5万至10万），其中大多数长度为12- 30aa，有2至3个二硫交联。在体外，形成生物学上相关的二硫化物结构往往是有问题的，这表明在体内，有效折叠多种螺毒素的机制已经由锥体蜗牛进化而来。我们在这里证明了Conus肽的正确折叠是由翻译后修饰的氨基酸γ -羧谷氨酸促进的。此外，我们发现蛋白质二硫异构酶的多种异构体是圆锥蛇毒管提取物的主要可溶性蛋白。这些结果为锥螺在系统地探索其他生物无法系统地进入的“微蛋白”的特殊生化世界之前所需的适应类型提供了证据。几乎可以肯定的是，需要额外的专门适应以实现高效的微蛋白折叠。
The 500 different species of venomous cone snails (genus Conus) use small, highly structured peptides (conotoxins) for interacting with prey, predators, and competitors. These peptides are produced by translating mRNA from many genes belonging to only a few gene superfamilies. Each translation product is processed to yield a great diversity of different mature toxin peptides (approximate to50,000100,000), most of which are 12-30 aa in length with two to three disulfide crosslinks. In vitro, forming the biologically relevant disulfide configuration is often problematic, suggesting that in vivo mechanisms for efficiently folding the diversity of conotoxins have been evolved by the cone snails. We demonstrate here that the correct folding of a Conus peptide is facilitated by a posttranslationally modified amino acid, gamma-carboxyglutamate. In addition, we show that multiple isoforms of protein disulfide isomerase are major soluble proteins in Conus venom duct extracts. The results provide evidence for the type of adaptations required before cone snails could systematically explore the specialized biochemical world of "microproteins" that other organisms have not been able to systematically access. Almost certainly, additional specialized adaptations for efficient microprotein folding are required.