State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
Sci Adv. 2022 Jul;8(26):eabn3868. doi: 10.1126/sciadv.abn3868. Epub 2022 Jul 1.
The mechanistic target of rapamycin-mLST8-raptor complex (mTORC1) functions as a central regulator of cell growth and metabolism in response to changes in nutrient signals such as amino acids. SAMTOR is an -adenosylmethionine (SAM) sensor, which regulates the mTORC1 activity through its interaction with the GTPase-activating protein activity toward Rags-1 (GATOR1)-KPTN, ITFG2, C12orf66 and SZT2-containing regulator (KICSTOR) complex. In this work, we report the crystal structures of SAMTOR in apo form and in complex with SAM. SAMTOR comprises an N-terminal helical domain and a C-terminal SAM-dependent methyltransferase (MTase) domain. The MTase domain contains the SAM-binding site and the potential GATOR1-KICSTOR-binding site. The helical domain functions as a molecular switch, which undergoes conformational change upon SAM binding and thereby modulates the interaction of SAMTOR with GATOR1-KICSTOR. The functional roles of the key residues and the helical domain are validated by functional assays. Our structural and functional data together reveal the molecular mechanism of the SAM sensing of SAMTOR and its functional role in mTORC1 signaling.
雷帕霉素靶蛋白-mLST8-雷帕霉素复合物（mTORC1）作为细胞生长和代谢的中央调节剂，可响应营养信号（如氨基酸）的变化而发挥作用。SAMTOR 是一种 - 腺苷甲硫氨酸（SAM）传感器，通过与 GTPase 激活蛋白活性向 Rag 蛋白-1（GATOR1）-KPTN、ITFG2、C12orf66 和 SZT2 组成的调节剂（KICSTOR）复合物相互作用，调节 mTORC1 活性。在这项工作中，我们报告了 SAMTOR 在 apo 形式和与 SAM 复合物中的晶体结构。SAMTOR 由一个 N 端螺旋结构域和一个 C 端 SAM 依赖性甲基转移酶（MTase）结构域组成。MTase 结构域包含 SAM 结合位点和潜在的 GATOR1-KICSTOR 结合位点。螺旋结构域作为分子开关，在 SAM 结合后发生构象变化，从而调节 SAMTOR 与 GATOR1-KICSTOR 的相互作用。通过功能测定验证了关键残基和螺旋结构域的功能作用。我们的结构和功能数据共同揭示了 SAMTOR 对 SAM 的分子感应机制及其在 mTORC1 信号中的功能作用。
