Cryo-EM structure of human mTOR complex 2
Cryo-EM structure of human mTOR complex 2
复制标题
人 mTOR 复合物 2 的冷冻电镜结构
DOI：
10.1038/s41422-018-0029-3
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发表时间：
2018-05-01
期刊：
影响因子：
44.1
通讯作者：
Xu, Yanhui
中科院分区：
文献类型：
--
作者：
Chen, Xizi;Liu, Mengjie;Xu, Yanhui
雷帕霉素（mTOR）复合物2（mTORC 2）通过磷酸化AGC蛋白激酶家族成员（包括AKT、PKC和SGK 1）在调节细胞增殖中起重要作用。功能性核心复合物由mTOR、mLST 8和两个mTORC 2特异性组分Rictor和mSin 1组成。在这里，我们研究了mTORC 2复合物内的分子间相互作用，并确定了其冷冻电子显微镜结构在4.9 μ m分辨率。该结构揭示了一个中空的菱面体褶皱与2倍对称。二聚化的mTOR充当复杂组装的支架。Rictor的N-末端一半由螺旋重复簇组成，并通过多个接触与mTOR结合。mSin 1位于mTOR的FRB结构域和催化腔附近。Rictor和mSin 1一起产生空间位阻以抑制FKBP 12-雷帕霉素与mTOR的结合，揭示了mTORC 2的雷帕霉素不敏感性的机制。mTORC 2中的mTOR二聚体显示出比mTORC 1（雷帕霉素敏感）更紧凑的构象，这可能是mTOR与Rictor-mSin 1之间相互作用的结果。结构比较显示Rictor和Raptor（mTORC 1特异性组分）与mTOR的结合是互斥的。我们的研究为理解mTORC 2的组装提供了基础，并为进一步研究mTORC 2通路的调控机制提供了框架。
Mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) plays an essential role in regulating cell proliferation through phosphorylating AGC protein kinase family members, including AKT, PKC and SGK1. The functional core complex consists of mTOR, mLST8, and two mTORC2-specific components, Rictor and mSin1. Here we investigated the intermolecular interactions within mTORC2 complex and determined its cryo-electron microscopy structure at 4.9 Å resolution. The structure reveals a hollow rhombohedral fold with a 2-fold symmetry. The dimerized mTOR serves as a scaffold for the complex assembly. The N-terminal half of Rictor is composed of helical repeat clusters and binds to mTOR through multiple contacts. mSin1 is located close to the FRB domain and catalytic cavity of mTOR. Rictor and mSin1 together generate steric hindrance to inhibit binding of FKBP12-rapamycin to mTOR, revealing the mechanism for rapamycin insensitivity of mTORC2. The mTOR dimer in mTORC2 shows more compact conformation than that of mTORC1 (rapamycin sensitive), which might result from the interaction between mTOR and Rictor-mSin1. Structural comparison shows that binding of Rictor and Raptor (mTORC1-specific component) to mTOR is mutually exclusive. Our study provides a basis for understanding the assembly of mTORC2 and a framework to further characterize the regulatory mechanism of mTORC2 pathway.