Mechanistic target of rapamycin （mTOR） complex 1 （mTORC1） integrates signals from growth factors, cel- lular energy levels, stress and amino acids to control cell growth and proliferation through regulating trans-...Mechanistic target of rapamycin （mTOR） complex 1 （mTORC1） integrates signals from growth factors, cel- lular energy levels, stress and amino acids to control cell growth and proliferation through regulating trans- lation, autophagy and metabolism. Here we determined the cryo-electron microscopy structure of human mTORC1 at 4.4 A resolution. The mTORCI comprises a dimer of heterotrimer （mTOR-Raptor-mLST8） mediated by the mTOR protein. The complex adopts a hollow rhomboid shape with 2-fold symmetry. Notably, mTORC1 shows intrinsic conformational dynamics. Within the complex, the conserved N-terminal caspase- like domain of Raptor faces toward the catalytic cavity of the kinase domain of mTOR. Raptor shows no caspase activity and therefore may bind to TOS motif for sub- strate recognition. Structural analysis indicates that FKBP12-Rapamycin may generate steric hindrance forsubstrate entry to the catalytic cavity of mTORCI. The structure provides a basis to understand the assembly of mTORC1 and a framework to characterize the regu- latory mechanism of mTORC1 pathway.展开更多
DearEditor,Eukaryotic transcription by RNA polymerase I(Pol I)is a strictly regulated process that involves the interplay of numerous factors.Promoter-proximal pausing is a regulatory mechanism that connects transcrip...DearEditor,Eukaryotic transcription by RNA polymerase I(Pol I)is a strictly regulated process that involves the interplay of numerous factors.Promoter-proximal pausing is a regulatory mechanism that connects transcription initiation and productive elongation in metazoans(Core and Adelman,2019).Pol II forms a paused elongation complex(PEC)through binding of two transcriptional regulation factors DSIF and NELF(Vos et al.,2018).Following the duration of pausing,Pol II either proceeds into productive elongation or undergoes promoter-proximal premature transcription termination(PTT)(Kamieniarz-Gdula and Proudfoot,2019),which plays a decisive role in determining transcriptional outputs.展开更多
基金We thank staff members Biomedical Core Facility, Fudan University and National Center for Protein Science Shanghai for their help on Mass Spectrometry analyses. We thank the Tsinghua Cryo-EM Facility and High Performance Computation Facility of National Center for Protein Science Beijing for their support in cryo-EM data collection and processing. This work was supported by Grants from the National Natural Science Foundation of China （Grant Nos. U1432242, 31425008, 91419301）, Basic Research Project of Shanghai Science and Technology Commission （No. 12JC1402700）, the Program of Shanghai Subject Chief Scientist （,No. 14XD1400500）.
文摘Mechanistic target of rapamycin （mTOR） complex 1 （mTORC1） integrates signals from growth factors, cel- lular energy levels, stress and amino acids to control cell growth and proliferation through regulating trans- lation, autophagy and metabolism. Here we determined the cryo-electron microscopy structure of human mTORC1 at 4.4 A resolution. The mTORCI comprises a dimer of heterotrimer （mTOR-Raptor-mLST8） mediated by the mTOR protein. The complex adopts a hollow rhomboid shape with 2-fold symmetry. Notably, mTORC1 shows intrinsic conformational dynamics. Within the complex, the conserved N-terminal caspase- like domain of Raptor faces toward the catalytic cavity of the kinase domain of mTOR. Raptor shows no caspase activity and therefore may bind to TOS motif for sub- strate recognition. Structural analysis indicates that FKBP12-Rapamycin may generate steric hindrance forsubstrate entry to the catalytic cavity of mTORCI. The structure provides a basis to understand the assembly of mTORC1 and a framework to characterize the regu- latory mechanism of mTORC1 pathway.
基金supported by grants from the National key R&D program of China(No.2021YFA1300100)the National Natural Science Foundation of China(Nos.32271308,32030055,31830107,and 31821002)+2 种基金the XPLORER Prize(YX.),the Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01)Shanghai Municipal Science and Technology Commission(No.19JC1411500)the Science and Technology Major Project of Inner Mongolia Autonomous Region of China to the State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock(No.2020ZD0008).
文摘DearEditor,Eukaryotic transcription by RNA polymerase I(Pol I)is a strictly regulated process that involves the interplay of numerous factors.Promoter-proximal pausing is a regulatory mechanism that connects transcription initiation and productive elongation in metazoans(Core and Adelman,2019).Pol II forms a paused elongation complex(PEC)through binding of two transcriptional regulation factors DSIF and NELF(Vos et al.,2018).Following the duration of pausing,Pol II either proceeds into productive elongation or undergoes promoter-proximal premature transcription termination(PTT)(Kamieniarz-Gdula and Proudfoot,2019),which plays a decisive role in determining transcriptional outputs.
