Crystal structure of the Gtr1p–Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation
Open accessAbstract
The target of rapamycin (TOR) complex 1 (TORC1) is a central cell growth regulator in response to a wide array of signals. The Rag GTPases play an essential role in relaying amino acid signals to TORC1 activation through direct interaction with raptor and recruitment of the TORC1 complex to lysosomes. Here we present the crystal structure of the Gtr1p–Gtr2p complex, the Rag homologs from Saccharomyces cerevisiae, at 2.8 Å resolution. The heterodimeric GTPases reveal a pseudo-twofold symmetric organization. Structure-guided functional analyses of RagA–RagC, the human homologs of Gtr1p–Gtr2p, show that both G domains (N-terminal GTPase domains) and dimerization are important for raptor binding. In particular, the switch regions of the G domain in RagA are indispensible for interaction with raptor, and hence TORC1 activation. The dimerized C-terminal domains of RagA–RagC display a remarkable structural similarity to MP1/p14, which is in a complex with lysosome membrane protein p18, and directly interact with p18, therefore recruiting mTORC1 to the lysosome for activation by Rheb. Our results reveal a structural model for the mechanism of the Rag GTPases in TORC1 activation and amino acid signaling.
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The crystal structure of Gtr1-Gtr2 confirmed that these GTPases heterodimerize using their roadblock domains analogously.
“The crystal structure of Gtr1-Gtr2 confirmed that these GTPases heterodimerize using their roadblock domains analogously (Gong et al., 2011).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Gong et al., 2011
In comparison to a Gtr1GMPPNP-Gtr2GMPPNP structure, the Gtr2GDP switch I region extends into an α-helix away from the nucleotide binding pocket with a concomitant global rotation, establishing a small novel interface between the GTPase domains whereby Gtr1 residues directly contact the Gtr2 nucleotide binding pocket and bound nucleotide itself.
“In comparison to a Gtr1GMPPNP-Gtr2GMPPNP structure (Gong et al., 2011), the Gtr2GDP switch I region extends into an α-helix away from the nucleotide binding pocket with a concomitant global rotation (Fig. 4D) establishing a small novel interface between the GTPase domains whereby Gtr1 residues directly contact the Gtr2 nucleotide binding pocket and bound nucleotide itself (Fig. 4E).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Gong et al., 2011
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- Authors
- Gong, R., Li, L., Liu, Y., Wang, P., Yang, H., Wang, L., Cheng, J., Guan, K.-L., & Xu, Y.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- University of California San Diego (US)
- Fudan University (CN)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-08-04
- Volume
- 25
- Issue
- 16
- Pages
- 1668-1673
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3165931
- OpenAlex
- W2148208138
- Cited by
- 98
- References
- 26
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 7 · 2019: 13 · 2018: 9 · 2017: 10 · 2016: 6 · 2015: 3 · 2014: 5 · 2013: 9 · 2012: 11
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Salt Science Research Foundation
- National Natural Science Foundation of China (31030019, 30870493)
- Science and Technology Commission of Shanghai Municipality
- Tsinghua University
- National Institutes of Health
- National Key Research and Development Program of China (2009CB918600)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Rag GTPases, amino acid signaling, p18, Rheb, Saccharomyces cerevisiae, crystal structure
- MeSH terms
- Amino Acids, Binding Sites, Enzyme Activation, Humans, Models, Molecular, Mutation, Protein Binding, Saccharomyces cerevisiae, Protein Structure, Tertiary, Crystallography, X-Ray, Phosphatidylinositol 3-Kinases, Amino Acid Substitution, Monomeric GTP-Binding Proteins, Saccharomyces cerevisiae Proteins, HEK293 Cells, TOR Serine-Threonine Kinases
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