Solution structure of APETx2, a specific peptide inhibitor of ASIC3 proton-gated channels
Solution structure of APETx2, a specific peptide inhibitor of ASIC3 proton-gated channels
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DOI：
10.1110/ps.051378905
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发表时间：
2005-08-01
期刊：
影响因子：
8
通讯作者：
Darbon, H
中科院分区：
文献类型：
--
作者：
Chagot, B;Escoubas, P;Darbon, H
酸敏感离子通道(ASIC)是一种质子门控钠离子通道，与炎症或缺血组织酸中毒相关的疼痛转导有关。APETx2是一种ASIC3的多肽毒素效应物，从海葵Anthopleura elegantissima的提取物中得到纯化。APETx2是一种由三个二硫键交联的42个氨基酸组成的多肽。它的三维结构，如传统的二维H-1-核磁共振所确定的那样，由一个由四链β-折叠组成的致密的二硫键核心组成。它属于富含二硫化物的全β结构家族，包括动物毒液中常见的多肽毒素。比较了APETx2和APETx1的结构特征，PcTX1是ASIC通道的另一个效应因子，但仅针对ASIC1a亚型，APETx1是一种结构上与APETx2相关的毒素，其靶向是HERG钾通道。结构比较，加上对这些不同离子通道效应器的静电特性的分析，我们提出了APETx2的一个可能的通道相互作用面，包括它的N端以及连接β链III和IV的I-β转角。这个碱性表面(R31和R17)也富含芳香残基(Y16，F15，Y32和F33)。连接β链I和II的由类型II‘-β转角组成的额外区域也可能在观察到这些不同的离子效应器的特异性方面发挥作用。
Acid-sensing ion channels (ASIC) are proton-gated sodium channels that have been implicated in pain transduction associated with acidosis in inflamed or ischemic tissues. APETx2, a peptide toxin effector of ASIC3, has been purified from an extract of the sea anemone Anthopleura elegantissima. APETx2 is a 42-amino-acid peptide cross-linked by three disulfide bridges. Its three-dimensional structure, as determined by conventional two-dimensional H-1-NMR, consists of a compact disulfide-bonded core composed of a four-stranded beta-sheet. It belongs to the disulfide-rich all-beta structural family encompassing peptide toxins commonly found in animal venoms. The structural characteristics of APETx2 are compared with that of PcTX1, another effector of ASIC channels but specific to the ASIC1a subtype and to APETx1, a toxin structurally related to APETx2, which targets the HERG potassium channel. Structural comparisons, coupled with the analysis of the electrostatic characteristics of these various ion channel effectors, led us to suggest a putative channel interaction surface for APETx2, encompassing its N terminus together with the type I-beta turn connecting beta-strands III and IV. This basic surface (R31 and R17) is also rich in aromatic residues (Y16, F15, Y32, and F33). An additional region made of the type II'-beta turn connecting beta-strands I and II could also play a role in the specificity observed for these different ion effectors.