Ragulator 作为 Rag GTPases 和 mTORC1 膜锚定的支架发挥作用的结构基础。
Structural basis for Ragulator functioning as a scaffold in membrane-anchoring of Rag GTPases and mTORC1.
机构信息
State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031, China.
School of Life Science and Technology, ShanghaiTech University, 393 Hua-Xia Zhong Road, Shanghai, 201210, China.
出版信息
Nat Commun. 2017 Nov 9;8(1):1394. doi: 10.1038/s41467-017-01567-4.
Amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) is mediated by Rag GTPases, which are recruited to the lysosome by the Ragulator complex consisting of p18, MP1, p14, HBXIP and C7orf59; however, the molecular mechanism is elusive. Here, we report the crystal structure of Ragulator, in which p18 wraps around the MP1-p14 and C7orf59-HBXIP heterodimers and the interactions of p18 with MP1, C7orf59, and HBXIP are essential for the assembly of Ragulator. There are two binding sites for the Roadblock domains of Rag GTPases: helix α1 of p18 and the two helices side of MP1-p14. The interaction of Ragulator with Rag GTPases is required for their cellular co-localization and can be competitively inhibited by C17orf59. Collectively, our data indicate that Ragulator functions as a scaffold to recruit Rag GTPases to lysosomal membrane in mTORC1 signaling.
氨基酸依赖性雷帕霉素靶蛋白复合体 1 (mTORC1) 的激活是由 Rag GTPases 介导的，Rag GTPases 通过由 p18、MP1、p14、HBXIP 和 C7orf59 组成的 Ragulator 复合物招募到溶酶体；然而，其分子机制尚不清楚。在这里，我们报告了 Ragulator 的晶体结构，其中 p18 包裹在 MP1-p14 和 C7orf59-HBXIP 异二聚体周围，p18 与 MP1、C7orf59 和 HBXIP 的相互作用对于 Ragulator 的组装是必不可少的。Rag GTPases 的 Roadblock 结构域有两个结合位点：p18 的α1 螺旋和 MP1-p14 的两个螺旋侧面。Ragulator 与 Rag GTPases 的相互作用是它们在细胞中共定位所必需的，并且可以被 C17orf59 竞争性抑制。总之，我们的数据表明，Ragulator 作为一种支架，在 mTORC1 信号转导中招募 Rag GTPases 到溶酶体膜。
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