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Crystal structure of eukaryotic translation initiation factor 2B

机译：真核翻译起始因子2B的晶体结构

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摘要

Eukaryotic cells restrict protein synthesis under various stress conditions, by inhibiting the eukaryotic translation initiation factor 2B (eIF2B)(1,2). eIF2B is the guanine nucleotide exchange factor for eIF2, a heterotrimeric G protein consisting of alpha-, beta- and gamma-subunits. eIF2B exchanges GDP for GTP on the.-subunit of eIF2 (eIF2.), and is inhibited by stress-induced phosphorylation of eIF2 alpha. eIF2B is a heterodecameric complex of two copies each of the alpha-, beta- and gamma-and e-subunits(3); its alpha-, beta- and delta-subunits constitute the regulatory subcomplex(4), while the gamma-and epsilon-subunits form the catalytic subcomplex(5). The three-dimensional structure of the entire eIF2B complex has not been determined. Here we present the crystal structure of Schizosaccharomyces pombe eIF2B with an unprecedented subunit arrangement, in which the alpha(2)beta(2)delta(2) hexameric regulatory subcomplex binds two.e dimeric catalytic subcomplexes on its opposite sides. A structure-based in vitro analysis by a surface-scanning site-directed photo-cross-linking method identified the eIF2a-binding and eIF2 gamma-binding interfaces, located far apart on the regulatory and catalytic subcomplexes, respectively. The eIF2 gamma-binding interface is located close to the conserved ` NF motif', which is important for nucleotide exchange. A structural model was constructed for the complex of eIF2B with phosphorylated eIF2 alpha, which binds to eIF2B more strongly than the unphosphorylated form. These results indicate that the eIF2 alpha phosphorylation generates the ` nonproductive' eIF2-eIF2B complex(5), which prevents nucleotide exchange on eIF2 gamma, and thus provide a structural framework for the eIF2B-mediated mechanism of stress-induced translational control.
机译：真核细胞通过抑制真核翻译起始因子2B（eIF2B）（1,2）来限制蛋白质在各种应激条件下的合成。 eIF2B是eIF2的鸟嘌呤核苷酸交换因子，eIF2是由α，β和γ亚基组成的异三聚体G蛋白。 eIF2B将GDP交换为eIF2.-亚基（eIF2。）上的GTP，并被应力诱导的eIF2α磷酸化所抑制。 eIF2B是一种异十聚体复合物，具有两个副本，每个副本分别包含α，β和γ亚基和e亚基（3）；它的α，β和δ亚基构成了调节亚复合物（4），而γ和ε亚基形成了催化亚复合物（5）。整个eIF2B复合体的三维结构尚未确定。在这里，我们介绍了具有前所未有的亚基排列的粟酒裂殖酵母eIF2B的晶体结构，其中alpha（2）beta（2）delta（2）六聚调节亚复合物在其相对侧结合了两个二聚催化亚复合物。通过表面扫描定点光交联法进行的基于结构的体外分析确定了分别位于调节亚复合物和催化亚复合物上的eIF2a结合和eIF2γ结合界面。 eIF2γ结合界面位于保守的“ NF基序”附近，这对核苷酸交换非常重要。针对eIF2B与磷酸化eIF2α的复合物构建了结构模型，该复合物比未磷酸化形式更牢固地与eIF2B结合。这些结果表明，eIF2α磷酸化产生了“非生产性” eIF2-eIF2B复合物（5），阻止了eIF2γ上的核苷酸交换，从而为eIF2B介导的应激诱导翻译控制机制提供了结构框架。

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  • 来源
    《Nature》 |2016年第7592期|122-125|共4页
  • 作者

    Kashiwagi Kazuhiro; Takahashi Mari; Nishimoto Madoka; Hiyama Takuya B.; Higo Toshiaki; Umehara Takashi; Sakamoto Kensaku; Ito Takuhiro; Yokoyama Shigeyuki;

  • 作者单位

    Univ Tokyo, Grad Sch Sci, Bunkyo Ku, Tokyo 1130033, Japan|RIKEN Syst & Struct Biol Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan|RIKEN Ctr Life Sci Technol, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan;

    RIKEN Ctr Life Sci Technol, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan;

    RIKEN Ctr Life Sci Technol, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan;

    Univ Tokyo, Grad Sch Sci, Bunkyo Ku, Tokyo 1130033, Japan|RIKEN Syst & Struct Biol Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan;

    RIKEN Syst & Struct Biol Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan|RIKEN Ctr Life Sci Technol, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan;

    RIKEN Syst & Struct Biol Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan|RIKEN Ctr Life Sci Technol, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan;

    RIKEN Syst & Struct Biol Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan|RIKEN Ctr Life Sci Technol, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan;

    Univ Tokyo, Grad Sch Sci, Bunkyo Ku, Tokyo 1130033, Japan|RIKEN Syst & Struct Biol Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan|RIKEN Ctr Life Sci Technol, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan;

    Univ Tokyo, Grad Sch Sci, Bunkyo Ku, Tokyo 1130033, Japan|RIKEN Syst & Struct Biol Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan|RIKEN Struct Biol Lab, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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