Novel alpha- and omega-conotoxins from Conus striatus venom.
Novel alpha- and omega-conotoxins from Conus striatus venom.
复制标题
来自纹状芋螺毒液的新型 α 和 omega 芋螺毒素。
DOI：
10.1021/bi00156a009
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发表时间：
1992
期刊：
影响因子：
2.9
通讯作者：
Olivera,BM
中科院分区：
文献类型：
--
作者：
Ramilo,CA;Zafaralla,GC;Nadasdi,L;Hammerland,LG;Yoshikami,D;Gray,WR;Kristipati,R;Ramachandran,J;Miljanich,G;Olivera,BM
1992年6月17日收到的修订稿件摘要：从圆锥蛇毒中提取了三种神经毒肽，并对其进行了生化表征和化学合成。其中一种是乙酰胆碱受体阻滞剂，命名为a-芋螺毒素SII，其序列为GCCCNPACGPNYGCGTSCS。与所有其他a-芋螺毒素不同的是，SII有三个二硫键(而不是两个)，没有净正电荷，并且有一个自由的C末端。另外两个麻痹多肽是钙通道靶向的W-芋螺毒素，Svia和SVIB。CO-svia是迄今为止鉴定的最小的天然w-芋螺毒素，其序列为CRSSGSPCGVTSICCGRCYRGKCT-NH2。虽然W-芋螺毒素svia在低等脊椎动物中是一种有效的麻痹毒素，但在哺乳动物中的效果要差得多。第三个毒素为W-芋螺毒素SVIB，其序列为CKLKGQSCRKTSYD-CCSGSCGRSGKC-NH2。这种多肽具有不同于以前从圆锥蛇毒中提纯的W-芋螺毒素的药理特异性；只有W-芋螺毒素SVIB被证明对小鼠注射后是致命的。与大鼠脑突触体膜的结合竞争实验表明，w-芋螺毒素SVIB的高亲和力结合部位不同于高亲和力w-芋螺毒素GVIA或MVIIA。大约500只圆锥属捕食性海洋蜗牛的毒液被用来麻痹猎物。大约有50个物种专门捕猎鱼类，并使用强有力的毒素来固定它们移动更快的猎物(Kohn等人，1960年)。以前已经证明，圆锥蛇毒中的麻痹成分是小肽，通常有10-30个氨基酸长[见Olivera等人(1990,1991)]。Conus多肽系统的一个意想不到的特征是极端的序列高度变异性，甚至在来自不同Conus物种的同源毒素之间也是如此(Olivera等人，1991年)。因此，在多肽家族中可以发现不同的氨基酸序列，其中所有多肽在鱼类猎物中具有相同的靶点(即，灭活在神经肌肉传递中重要的特定受体或离子通道)。这种超变异性在神经科学中有潜在的用处。在哺乳动物中枢神经系统的进化过程中，显然发生了不同受体亚型的巨大增殖。圆锥虫毒素家族被证明对研究和区分密切相关的受体亚型是有用的。当这些序列不同但同源的芋螺毒素在复杂的神经系统(如哺乳动物的大脑)中进行测试时，任何两个同源的Conus多肽往往表现出一些不同的(但通常是重叠的)结合特性。重组DNA技术识别的受体亚型的多样性产生了扩大互补药理探针的收集的需要；
Revised Manuscript Received June 17, 1992 abstract: Three neurotoxic peptides from the venom of Conus striatus have been purified, biochemically characterized, and chemically synthesized. One of these, an acetylcholine receptor blocker designated a-conotoxin SII, has the sequence GCCCNPACGPNYGCGTSCS. In contrast to all other a-conotoxins, SII has three disulfide bonds (instead of two), has no net positive charge, and has a free C-terminus. The other two paralytic peptides are Ca channel-targeted w-conotoxins, SVIA and SVIB. co-SVIA is the smallest natural w-conotoxin so far characterized and has the sequence CRSSGSPCGVTSICCGRCYRGKCT-NH2. Although w-conotoxin SVIA is a potent paralytic toxic in lower vertebrate species, it was much less effective in mammals. The third toxin, w-conotoxin SVIB, has the sequence CKLKGQSCRKTSYD-CCSGSCGRSGKC-NH2. This peptide has a different pharmacological specificity from otherw-conotoxins previously purified from Conus venoms; only w-conotoxin SVIB has proven to be lethal to miceupon ic injection. Binding competition experiments with rat brain synaptosomal membranes indicate that the high-affinity binding site for w-conotoxin SVIB is distinct from the high-affinity w-conotoxin GVIA or MVIIA site.The venoms of the ca. 500 predatory marine snails belonging to the genus Conus are used to paralyze prey. Approximately 50 species hunt fish exclusively and employ potent toxins to immobilize their faster moving prey (Kohn et al., 1960). It has previously been shown that the paralytic components in Conus venoms are small peptides, typically 10-30amino acids long [see Olivera et al.(1990, 1991)]. One unexpected feature of the Conus peptide system is the extreme sequence hypervariability, even among homologous toxins from different Conus species (Olivera et al., 1991). Thus, diverse amino acid sequences can be found within a peptide family wherein all peptides have the same target in the fish prey (ie, inactivating a specific receptor or ion channel important in neuromuscular transmission). This hypervari-ability is potentially useful in neuroscience. An enormous proliferation of different receptor subtypes has apparently taken place in the evolution of the mammalian central nervous system. Families of Conus toxins are proving to be useful for studying and distinguishing closely related receptor subtypes. When these sequence-divergent but homologous conotoxins are tested in a complex nervous system such as mammalian brain, any two homologous Conus peptides often exhibit somewhat different (but usually overlapping) binding spec-ificities. The multiplicity of receptor subtypes being identified by recombinant DNA technology creates a need to enlarge the collection of complementary pharmacological probes; the