高阶磷酸酶-底物接触终止了综合应力响应

IF 16.8 1区 生物学
Yahui Yan, H. Harding, D. Ron
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引用次数: 6

摘要

许多调节性PPP1R亚基与少数催化性PP1c亚基结合,介导后生动物中的磷酸丝氨酸和磷酸苏氨酸去磷酸化。调节亚基与PP1c的表面结合,局部影响磷酸肽灵活进入活性位点。然而,全磷酸酶对其磷蛋白底物的催化效率仍然无法解释。在这里,我们提出了一种三重PP1c–PPP1R15A–G-肌动蛋白全磷酸酶的冷冻电镜结构,该结构终止了哺乳动物综合应激反应(ISR)中与其底物翻译起始因子2α(eIF2α)的脱磷前复合物中的信号传导。G-肌动蛋白在eIF2α去磷酸化中的重要作用在晶体学、生物化学和遗传学上得到支持,它排列催化和调节亚基,形成一个与eIF2α的N-末端结构域结合的复合表面,将远处的磷酸丝氨酸-51定位在活性位点。介导对全磷酸酶亲和力的底物残基也与eIF2α激酶进行关键接触。因此,高阶底物识别的收敛过程指定了ISR中功能拮抗的磷酸化和去磷酸化。磷酸化eIF2α的去磷酸化复合物的结构揭示了与调节性PPP1R15A亚基的接触如何介导底物选择性,为不同组合组装的全磷酸酶的去磷酸反应提供了范例。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Higher-order phosphatase–substrate contacts terminate the integrated stress response
Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally affecting flexible access of the phosphopeptide to the active site. However, catalytic efficiency of holophosphatases towards their phosphoprotein substrates remains unexplained. Here we present a cryo-EM structure of the tripartite PP1c–PPP1R15A–G-actin holophosphatase that terminates signaling in the mammalian integrated stress response (ISR) in the pre-dephosphorylation complex with its substrate, translation initiation factor 2α (eIF2α). G-actin, whose essential role in eIF2α dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2α to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2α kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR. Structures of the dephosphorylation complex for phosphorylated eIF2α reveal how contacts with the regulatory PPP1R15A subunit mediate substrate selectivity, providing a paradigm for dephosphorylation reactions by diverse combinatorially assembled holophosphatases.
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来源期刊
Nature Structural &Molecular Biology
Nature Structural &Molecular Biology 生物-生化与分子生物学
自引率
1.80%
发文量
160
期刊介绍: Nature Structural & Molecular Biology is a monthly journal that focuses on the functional and mechanistic understanding of how molecular components in a biological process work together. It serves as an integrated forum for structural and molecular studies. The journal places a strong emphasis on the functional and mechanistic understanding of how molecular components in a biological process work together. Some specific areas of interest include the structure and function of proteins, nucleic acids, and other macromolecules, DNA replication, repair and recombination, transcription, regulation of transcription and translation, protein folding, processing and degradation, signal transduction, and intracellular signaling.
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