EMD-10133
cryo-EM structure of mTORC1 bound to active RagA/C GTPases
EMD-10133
Single-particle6.2 Å
Deposition: 18/07/2019
Map released: 16/10/2019
Last modified: 22/05/2024
Sample Organism:
Homo sapiens
Sample: cryo-EM structure of mTORC1 bound to active RagA/C complex
Fitted models: 6sb2 (Avg. Q-score: 0.211)
Deposition Authors: Anandapadamanaban M , Berndt A
Sample: cryo-EM structure of mTORC1 bound to active RagA/C complex
Fitted models: 6sb2 (Avg. Q-score: 0.211)
Deposition Authors: Anandapadamanaban M , Berndt A
Architecture of human Rag GTPase heterodimers and their complex with mTORC1.
Anandapadamanaban M ,
Masson GR ,
Perisic O ,
Berndt A ,
Kaufman J ,
Johnson CM ,
Santhanam B ,
Rogala KB ,
Sabatini DM ,
Williams RL
(2019) Science , 366 , 203 - 210
(2019) Science , 366 , 203 - 210
Abstract:
The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.
The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.