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Structure paper

TitleArchitecture of human Rag GTPase heterodimers and their complex with mTORC1.
Journal, issue, pagesScience, Vol. 366, Issue 6462, Page 203-210, Year 2019
Publish dateOct 11, 2019
AuthorsMadhanagopal Anandapadamanaban / Glenn R Masson / Olga Perisic / Alex Berndt / Jonathan Kaufman / Chris M Johnson / Balaji Santhanam / Kacper B Rogala / David M Sabatini / Roger L Williams /
PubMed AbstractThe 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 ...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.
External linksScience / PubMed:31601764 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.5 - 6.2 Å
Structure data

10132

6sb0

EMDB-10132, PDB-6sb0:
cryo-EM structure of mTORC1 bound to PRAS40-fused active RagA/C GTPases
Method: EM (single particle) / Resolution: 5.5 Å

10133

6sb2

EMDB-10133, PDB-6sb2:
cryo-EM structure of mTORC1 bound to active RagA/C GTPases
Method: EM (single particle) / Resolution: 6.2 Å

PDB-6s6a:
Crystal structure of RagA-Q66L/RagC-T90N GTPase heterodimer complex
Method: X-RAY DIFFRACTION / Resolution: 2.63 Å

PDB-6s6d:
Crystal structure of RagA-Q66L-GTP/RagC-S75N-GDP GTPase heterodimer complex
Method: X-RAY DIFFRACTION / Resolution: 2.5 Å

Chemicals

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM / Guanosine triphosphate

ChemComp-MG:
Unknown entry

ChemComp-9JE:
pentane-1,5-diol / Pentane-1,5-diol

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM / Guanosine diphosphate

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / small GTPases / mTORC1 activator / roadblock domain / GTPase domain

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