美国麻省理工学院David M. Sabatini研究团队发现mTORC1与溶酶体表面对接的结构基础。这一研究成果2019年10月10日在线发表于《科学》。

mTORC1蛋白激酶响应营养物和生长因子来调节生长。营养促进其向溶酶体表面的转运，在溶酶体表面，其Raptor亚基与Rag GTPase调控子复合物相互作用。营养成分会在四种不同的核苷酸结合状态之间切换异二聚体Rag GTPases，其中只有一种（RagA / B•GTP–RagC / D•GDP）允许mTORC1缔合。

研究人员通过冷冻电子显微镜确定了具有Rag调控子的Raptor超级复合物的结构，分辨率为3.2Å。Raptor α-螺线肌醇直接检测RagA的核苷酸状态，而Raptor “爪”穿过GTPase结构域之间以检测RagC的核苷酸状态。破坏Rag-Raptor结合的突变会抑制mTORC1溶酶体的定位和信号传导。通过与其激活剂Rheb结合的mTORC1的结构进行比较，他们开发了附着在溶酶体上的活性mTORC1模型。

附：英文原文

Title: Structural basis for the docking of mTORC1 on the lysosomal surface

Author: Kacper B. Rogala, Xin Gu, Jibril F. Kedir, Monther Abu-Remaileh, Laura F. Bianchi, Alexia M. S. Bottino, Rikke Dueholm, Anna Niehaus, Daan Overwijn, Ange-Célia Priso Fils, Sherry X. Zhou, Daniel Leary, Nouf N. Laqtom, Edward J. Brignole, David M. Sabatini

Issue&Volume: 2019/10/10

Abstract: 

The mTORC1 protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where its Raptor subunit interacts with the Rag GTPase-Ragulator complex. Nutrients switch the heterodimeric Rag GTPases between four different nucleotide binding states, only one of which (RagA/B•GTP–RagC/D•GDP) permits mTORC1 association. We determined the structure of the supercomplex of Raptor with Rag-Ragulator to 3.2 Å resolution by cryo-electron microscopy. The Raptor α-solenoid directly detects the nucleotide state of RagA, while the Raptor “claw” threads between the GTPase domains to detect that of RagC. Mutations that disrupt Rag-Raptor binding inhibit mTORC1 lysosomal localization and signaling. By comparison with a structure of mTORC1 bound to its activator Rheb, we develop a model of active mTORC1 docked on the lysosome.

DOI: 10.1126/science.aay0166

Source:https://science.sciencemag.org/content/early/2019/10/10/science.aay0166