Spanish National Cancer Research Centre (CNIO), Structural Biology Programme, Melchor Fernández Almagro 3, Madrid, Spain.
Subcell Biochem. 2024;104:459-483. doi: 10.1007/978-3-031-58843-3_17.
The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth and metabolism, integrating environmental signals to regulate anabolic and catabolic processes, regulating lipid synthesis, growth factor-induced cell proliferation, cell survival, and migration. These activities are performed as part of two distinct complexes, mTORC1 and mTORC2, each with specific roles. mTORC1 and mTORC2 are elaborated dimeric structures formed by the interaction of mTOR with specific partners. mTOR functions only as part of these large complexes, but their assembly and activation require a dedicated and sophisticated chaperone system. mTOR folding and assembly are temporarily separated with the TELO2-TTI1-TTI2 (TTT) complex assisting the cotranslational folding of mTOR into a native conformation. Matured mTOR is then transferred to the R2TP complex for assembly of active mTORC1 and mTORC2 complexes. R2TP works in concert with the HSP90 chaperone to promote the incorporation of additional subunits to mTOR and dimerization. This review summarizes our current knowledge on how the HSP90-R2TP-TTT chaperone system facilitates the maturation and assembly of active mTORC1 and mTORC2 complexes, discussing interactions, structures, and mechanisms.
雷帕霉素靶蛋白（mTOR）是细胞生长和代谢的主要调节剂，整合环境信号以调节合成代谢和分解代谢过程，调节脂质合成、生长因子诱导的细胞增殖、细胞存活和迁移。这些活动是作为两个不同复合物 mTORC1 和 mTORC2 的一部分进行的，每个复合物都有特定的作用。mTORC1 和 mTORC2 是由 mTOR 与特定伴侣相互作用形成的二聚体结构。mTOR 仅作为这些大型复合物的一部分发挥作用，但它们的组装和激活需要专门且复杂的伴侣系统。mTOR 的折叠和组装是暂时分离的，TELO2-TTI1-TTI2（TTT）复合物辅助 mTOR 共翻译折叠成天然构象。成熟的 mTOR 然后转移到 R2TP 复合物，以组装活性 mTORC1 和 mTORC2 复合物。R2TP 与 HSP90 伴侣蛋白协同作用，促进额外亚基与 mTOR 的结合和二聚化。这篇综述总结了我们目前对 HSP90-R2TP-TTT 伴侣系统如何促进活性 mTORC1 和 mTORC2 复合物的成熟和组装的了解，讨论了相互作用、结构和机制。
