Architecture of the human GATOR1 and GATOR1–Rag GTPases complexes
Open accessAbstract
Nutrients, such as amino acids and glucose, signal through the Rag GTPases to activate mTORC1. The GATOR1 protein complex-comprising DEPDC5, NPRL2 and NPRL3-regulates the Rag GTPases as a GTPase-activating protein (GAP) for RAGA; loss of GATOR1 desensitizes mTORC1 signalling to nutrient starvation. GATOR1 components have no sequence homology to other proteins, so the function of GATOR1 at the molecular level is currently unknown. Here we used cryo-electron microscopy to solve structures of GATOR1 and GATOR1-Rag GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 links DEPDC5 and NPRL3, and DEPDC5 contacts the Rag GTPase heterodimer. Biochemical analyses reveal that our GATOR1-Rag GTPases structure is inhibitory, and that at least two binding modes must exist between the Rag GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity. These data reveal the structure of a component of the nutrient-sensing mTORC1 pathway and a non-canonical interaction between a GAP and its substrate GTPase.
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The structure of the mammalian GATOR1 complex was recently resolved by cryo-EM, revealing the architecture of each GATOR1 component and the structure of a stable complex with the Rag GTPases.
“While GATOR2 remains structurally uncharacterised, the structure of the mammalian GATOR1 complex was recently resolved by cryo-EM (Shen et al., 2018), revealing the architecture of each GATOR1 component (Fig. 3A) and the structure of a stable complex with the Rag GTPases (Fig. 3B).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Shen et al., 2018
GATOR1 is presumed to interact with the Rag heterodimer in two ways: an inhibitory conformation that binds GTP-bound RagA with higher relative affinity but insufficient to activate GTP hydrolysis, and a lower-affinity interaction dependent on the NPRL2-NPRL3 heterodimer that stimulates GTPase activity.
“GATOR1 is thus presumed to interact with the Rag heterodimer in two ways: the ‘inhibitory’ conformation, captured in the resolved cryo-EM structure, which binds to GTP-bound RagA with higher relative affinity but insufficient to activate GTP hydrolysis, and a lower-affinity interaction dependent on the NPRL2-NPRL3 heterodimer that stimulates GTPase activity.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Shen et al., 2018
NPRL2 and NPRL3 are believed to constitute the GATOR2 binding site of GATOR1.
“It is important to note that NPRL2 and NPRL3 are believed to constitute the GATOR2 binding site of GATOR1 (Shen et al., 2018).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Shen et al., 2018
The RagC-bound ligand in the GATOR1-Rag structure is thought to be GDP because RagC contains a S75N mutation which induces preferential GDP binding.
“Although the resolution of the cryo-EM structure was insufficient to accurately identify the RagC-bound ligand, it is thought to be GDP as RagC contains a S75N mutation which induces preferential GDP binding (Shen et al., 2018).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Shen et al., 2018
A notable difference between both GTPase domains is the conformation of switch I, which in RagC appears to have extended and broken the central β-sheet as seen in RagA.
“A notable difference between both GTPase domains is the conformation of switch I, which in RagC appears to have extended and broken the central β-sheet as seen in RagA.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Shen et al., 2018
The GATOR1-Rag structure has provided the first glimpse of the Rag GTPase domains within the heterodimer.
“The GATOR1-Rag structure has provided the first glimpse of the Rag GTPase domains within the heterodimer (Shen et al., 2018) (Fig. 4C).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Shen et al., 2018
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- Authors
- Shen, K., Huang, R. K., Brignole, E. J., Condon, K. J., Valenstein, M. L., Chantranupong, L., Bomaliyamu, A., Choe, A., Hong, C., Yu, Z., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Yu, Zhiheng
- Sabatini, David M.
- ORCID
- Venue
- Nature
- Published
- 2018-03-28
- Volume
- 556
- Issue
- 7699
- Pages
- 64-69
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5975964
- OpenAlex
- W2794845581
- Cited by
- 192
- References
- 40
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 23 · 2023: 20 · 2022: 28 · 2021: 26 · 2020: 27 · 2019: 18 · 2018: 10
- FWCI
- 7.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- National Cancer Institute (R01CA103866, R01CA129105)
- National Institute of General Medical Sciences (T32GM007753, T32GM007287)
- National Institute of Allergy and Infectious Diseases (R37AI047389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- GATOR1 complex, Rag GTPases, raga, mTORC1 signaling, nutrient sensing, GTPase-activating protein, DEPDC5, NPRL2, NPRL3, protein complex structure, GTP hydrolysis, amino acid signalling, glucose signalling, nutrient deprivation, growth regulation
- MeSH terms
- Protein Domains, Mechanistic Target of Rapamycin Complex 1, Amino Acids, Guanosine Triphosphate, Humans, Hydrolysis, Models, Molecular, Protein Binding, Repressor Proteins, Cryoelectron Microscopy, Monomeric GTP-Binding Proteins, GTPase-Activating Proteins, Protein Subunits, Tumor Suppressor Proteins, Multiprotein Complexes, Protein Multimerization
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