Human apo-SRP72 and SRP68/72 complex structures reveal the molecular basis of protein translocation

文献类型： 外文期刊

第一作者： Gao, Yina

作者： Gao, Yina;Liu, Yang;Dong, Xiaofei;Chen, Zhenhang;Tang, Jun;Wu, Wei;Chen, Zhongzhou;Zhang, Qi;Tong, Yufeng;Lang, Yue;Tang, Jun;Tian, Wenli;Tong, Yufeng

作者机构：

关键词： SRP72;SRP68;protein translocation;crystal structures;cancer;protein-protein interaction;signal recognition particle

期刊名称：JOURNAL OF MOLECULAR CELL BIOLOGY （ 影响因子：6.216； 五年影响因子：6.688 ）

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年卷期：

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收录情况： SCI

摘要： 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 2.91A and 1.7A 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.

分类号： R393

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