6S6D

Crystal structure of RagA-Q66L-GTP/RagC-S75N-GDP GTPase heterodimer complex

Summary for 6S6D

• Entry DOI: 10.2210/pdb6s6d/pdb
• Descriptor: Ras-related GTP-binding protein A, Ras-related GTP-binding protein C, GUANOSINE-5'-TRIPHOSPHATE, ... (7 entities in total)
• Functional Keywords: small gtpases, mtorc1 activator, roadblock domain, gtpase domain, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 163987.78

Authors

Anandapadamanaban, M.,Masson, G.R.,Perisic, O.,Kaufman, J.,Williams, R.L. (deposition date: 2019-07-02, release date: 2019-10-16, Last modification date: 2024-05-15)

Primary citation

Anandapadamanaban, M.,Masson, G.R.,Perisic, O.,Berndt, A.,Kaufman, J.,Johnson, C.M.,Santhanam, B.,Rogala, K.B.,Sabatini, D.M.,Williams, R.L.
Architecture of human Rag GTPase heterodimers and their complex with mTORC1.
Science, 366:203-210, 2019

PubMed 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 RagA/RagC 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.

PubMed: 31601764
DOI: 10.1126/science.aax3939

Experimental method

X-RAY DIFFRACTION (2.5 Å)