Human apo-SRP72 and SRP68/72 complex structures reveal the molecular basis of protein translocation.
Human apo-SRP72 and SRP68/72 complex structures reveal the molecular basis of protein translocation.
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人apo-SRP72和SRP68/72复合物结构揭示了蛋白质易位的分子基础
DOI：
10.1093/jmcb/mjx010
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发表时间：
2017-06-01
影响因子：
5.5
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Gao Y;Zhang Q;Lang Y;Liu Y;Dong X;Chen Z;Tian W;Tang J;Wu W;Tong Y;Chen Z
分泌蛋白和膜蛋白的共翻译靶向或插入内质网(ER)是信号识别颗粒(SRP)介导的一个关键生物学过程。在真核生物中，SRP68-SRP72(SRP68/72)异源二聚体在蛋白质转运中起着至关重要的作用。然而，关于两个最大的SRP蛋白SRP68和SRP72的结构信息有限，特别是关于它们之间的相互作用。在这里，我们首次报道了人apo-SRP72和SRP68/72复合体的晶体结构，分辨率分别为2.91？和1.7？SRP72的SRP68结合区含有四个非典型的四肽重复序列(TPR)和一个灵活的C-端帽。Apo-SRP72主要以二聚体形式存在于溶液中。为了与SRP68结合，SRP72同源二聚体解离，不可或缺的C-端帽经历了显著的构象变化，以帮助SRP68/72异二聚体的形成。SRP68的23个残基的多肽足以通过其异常疏水和延伸的表面与SRP72紧密结合。结构、生物物理和突变分析表明，癌症相关突变破坏了SRP68-SRP72在哺乳动物细胞中的相互作用及其与ER的共同定位。这些结果突出了SRP68-SRP72相互作用在SRP介导的蛋白质易位中的重要作用，并为疾病诊断、病理生理学和药物设计提供了结构基础。
The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum (ER) is a key biological process mediated by the signal recognition particle (SRP). In eukaryotes, the SRP68–SRP72 (SRP68/72) heterodimer plays an essential role in protein translocation. However, structural information on the two largest SRP proteins, SRP68 and SRP72, is limited, especially regarding their interaction. Herein, we report the first crystal structures of human apo-SRP72 and the SRP68/72 complex at 2.91Å and 1.7Å resolution, respectively. The SRP68-binding domain of SRP72 contains four atypical tetratricopeptide repeats (TPR) and a flexible C-terminal cap. Apo-SRP72 exists mainly as dimers in solution. To bind to SRP68, the SRP72 homodimer disassociates, and the indispensable C-terminal cap undergoes a pronounced conformational change to assist formation of the SRP68/72 heterodimer. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 through its unusually hydrophobic and extended surface. Structural, biophysical, and mutagenesis analyses revealed that cancer-associated mutations disrupt the SRP68–SRP72 interaction and their co-localization with ER in mammalian cells. The results highlight the essential role of the SRP68–SRP72 interaction in SRP-mediated protein translocation and provide a structural basis for disease diagnosis, pathophysiology, and drug design.
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影响因子：
4.8
作者：
Grizot, S;Fieschi, F;Pebay-Peyroula, E
通讯作者：
Pebay-Peyroula, E
DOI：
10.1073/pnas.0402231101
发表时间：
2004-05-25
影响因子：
11.1
作者：
Buskiewicz, I;Deuerling, E;Wintermeyer, W
通讯作者：
Wintermeyer, W
影响因子：
4.8
作者：
Fukuhara, N;Fernandez, E;Svergun, D
通讯作者：
Svergun, D
影响因子：
8
作者：
Iakhiaeva, Elena;Bhuiyan, Shakhawat Hossain;Zwieb, Christian
通讯作者：
Zwieb, Christian
影响因子：
16.6
作者：
Jomaa A;Boehringer D;Leibundgut M;Ban N
通讯作者：
Ban N