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首页> 外文期刊>Biochemistry >A single amino acid replacement results in the Ca2+-induced self-assembly of a helical conantokin-based peptide
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A single amino acid replacement results in the Ca2+-induced self-assembly of a helical conantokin-based peptide

机译：单个氨基酸替换导致基于螺旋螺壳蛋白的肽的Ca2 +诱导的自组装

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摘要

Conantokins are short (17-27 amino acid residues), gamma-carboxyglutamate (Gla)-rich peptide components of the venoms of marine snails of the genus Conus. They display high apo and/or Ca2+-induced helicity and act as potent and selective inhibitors of the N-methyl-D-aspartate receptor (NMDAR). We have previously established that one of the conantokins, conantokin-G (con-G), self-associates in the presence of Ca2+ with high specificity for antiparallel chain orientation [Dai, Q., Prorok, M., and Castellino, F. J. (2004) J. Mol. Biol. 336, 731-744]. The dimerization appears to be driven by interhelical Ca2+ coordination between the following residue pairings: Gla(3)-Gla(14), Gla(7)-Gla(10'), Gla(10)-Gla(7'), and Gla(14)-Gla(3'). A second member of the conantokin family, conantokin-T (con-T), shares sequence identity with con-G at 8 of 21 amino acids, including 4 Gla residues. These similarities notwithstanding, several primary and secondary structural differences exist between con-T and con-G. Particularly notable is that con-T contains a Lys, rather than a Gla, at position 7. Moreover, unlike con-G, con-T does not undergo Ca(2+)triggered self-assembly. In the present study, sedimentation equilibrium ultracentrifugation is employed to demonstrate that a single amino acid replacement analogue of con-T, con-T[K7gamma], assumes a dimeric superstructure in the presence of Ca2+ at pH values consistent with the ionization of Gla carboxylate groups. Further-more, HPLC-monitored thiol-disulfide folding and rearrangement assays with Cys-containing con-T variants suggest that the relative chain alignment preference in the noncovalent complex is antiparallel. Our results suggest that interchain Ca2+ coordination in con-T[K7gamma] is incumbent upon an "i, i + 4, i + 7, i + 11" arrangement of Gla residues, as occurs in native con-G.
机译：Conantokins是Conus属海洋蜗牛毒液中短的（富含17-27个氨基酸残基）富含γ-羧基谷氨酸（Gla）的肽成分。它们显示出高载脂蛋白和/或Ca2 +诱导的螺旋度，并充当N-甲基-D-天冬氨酸受体（NMDAR）的有效和选择性抑制剂。我们以前已经确定，伴刀豆素之一，伴刀豆素G（con-G），在Ca2 +存在下自缔合，对反平行链取向具有高度特异性[Dai，Q.，Prorok，M.和Castellino，FJ（ 2004）J.Mol。生物学336，731-744]。二聚化似乎是由以下残基配对之间的螺旋间Ca2 +配位驱动的：Gla（3）-Gla（14），Gla（7）-Gla（10'），Gla（10）-Gla（7'）和Gla （14）-Gla（3′）。 conantokin-T（con-T）是conantokin家族的第二个成员，与con-G在21个氨基酸中的8个（包括4个Gla残基）上具有序列同一性。尽管有这些相似之处，但是con-T和con-G之间存在一些主要和次要结构差异。特别值得注意的是，con-T在位置7处包含Lys而不是Gla。而且，与con-G不同，con-T并未经历Ca（2+）触发的自组装。在本研究中，采用沉降平衡超速离心法证明，在Ca2 +存在下，pH值与Gla羧酸盐的电离一致的con-T的单个氨基酸替代类似物con-T [K7γ]呈现二聚体超结构。组。此外，使用含Cys的con-T变体的HPLC监测的巯基-二硫键折叠和重排分析表明，非共价复合物中的相对链排列偏好是反平行的。我们的结果表明，与天然con-G一样，con-T [K7γ]中的链间Ca 2+配位是Gla残基的“ i，i + 4，i + 7，i + 11”排列。

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