Crystal Structure of the α Subunit of Human Translation Initiation Factor 2B
Crystal Structure of the α Subunit of Human Translation Initiation Factor 2B
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DOI：
10.1016/j.jmb.2009.07.054
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发表时间：
2009-10-02
影响因子：
5.6
通讯作者：
Yokoyama, Shigeyuki
中科院分区：
文献类型：
--
作者：
Hiyama, Takuya B.;Ito, Takuhiro;Yokoyama, Shigeyuki
真核细胞翻译起始因子2B(EIF2B)是真核细胞起始因子2(6172)所特有的异五聚体鸟嘌呤核苷酸交换因子。在应激条件下，磷酸化的eIF2与eIF2B的紧密结合强烈地抑制了鸟嘌呤-核苷酸交换。在这里，我们报道了2.65埃分辨率下人类eIF2Bα亚基的晶体结构。EIF2Bα结构由N端的α螺旋结构域和C端的Rossmann折叠结构域组成。一个带正电的口袋，入口处直径约为15-17埃，位于两个区域之间的边界上。硫酸盐离子位于袋的底部(深度约16埃)。组成硫酸盐离子结合位点的残基在eIF2Bα中严格保守。由于这个带有硫酸盐离子结合部位的深而宽的口袋在遥远的同源物中不保守，包括5-甲硫代核糖1-磷酸异构酶，这些特征可能是eIF2Bα的独特特征。有趣的是，酵母eIF2Bα错义突变降低了eIF2B对磷酸化eIF2的敏感性，被定位在口袋的另一侧。三个人类eIFB2B阿尔法错义突变之一，导致致命的脑部疾病，脑白质消失或儿童共济失调伴中枢神经系统髓鞘减少，被映射到口袋里。EIF2B的β和Delta亚基与eIF2Bα同源，并且可能具有类似于目前的eIF2Bα结构的三级结构。EIF2Bα与硫酸盐离子结合的残基在eIF2Bβ/Delta中保守。上述酵母和人类eIF2Bβ/Delta错义突变也被定位在eIF2Bα结构上，表明人类突变与口袋聚集在同一侧，而酵母突变位于相反的一侧。由于大多数突变残基暴露在eIF2B亚基结构的表面，这些暴露的残基可能参与亚基相互作用或与eIF2的相互作用。(C)2009爱思唯尔有限公司。保留所有权利。
Eukaryotic translation initiation factor 2B (eIF2B) is the heteropentameric guanine-nucleotide exchange factor specific for eukaryotic initiation factor 2 (6172). Under stressed conditions, guanine-nucleotide exchange is strongly inhibited by the tight binding of phosphorylated eIF2 to eIF2B. Here, we report the crystal structure of the alpha subunit of human eIF2B at 2.65 angstrom resolution. The eIF2B alpha structure consists of the N-terminal alpha-helical domain and the C-terminal Rossmann-fold-like domain. A positively charged pocket, whose entrance is about 15-17 angstrom in diameter, resides at the boundary between the two domains. A sulfate ion is located at the bottom of the pocket (about 16 angstrom in depth). The residues comprising the sulfate-ion-binding site are strictly conserved in eIF2B alpha. Since this deep, wide pocket with the sulfate-ion-binding site is not conserved in distant homologues, including 5-methylthioribose 1-phosphate isomerases, these characteristics may be distinctive of eIF2B alpha. Interestingly, the yeast eIF2B alpha missense mutations that reduce the eIF2B sensitivity to phosphorylated eIF2 are mapped on the other side of the pocket. One of the three human eIFB2B alpha missense mutations that induce the lethal brain disorder vanishing white matter or childhood ataxia with central nervous system hypomyelination is mapped inside the pocket. The beta and delta subunits of eIF2B are homologous to eIF2B alpha and may have tertiary structures similar to the present eIF2B alpha structure. The sulfate-ion-binding residues of eIF2B alpha are well conserved in eIF2B beta/delta. The abovementioned yeast and human missense mutations of eIF2B beta/delta were also mapped on the eIF2B alpha structure, which revealed that the human mutations are clustered on the same side as the pocket, while the yeast mutations reside on the opposite side. As most of the mutated residues are exposed on the surface of the eIF2B subunit structure, these exposed residues are likely to be involved in either the subunit interactions or the interaction with eIF2. (C) 2009 Elsevier Ltd. All rights reserved.