Crystal Structure of the Gtr1pGTP-Gtr2pGDP Protein Complex Reveals Large Structural Rearrangements Triggered by GTP-to-GDP Conversion
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The heterodimeric Rag GTPases consisting of RagA (or RagB) and RagC (or RagD) are the key regulator activating the target of rapamycin complex 1 (TORC1) in response to the level of amino acids. The heterodimer between GTP-loaded RagA/B and GDP-loaded RagC/D is the most active form that binds Raptor and leads to the activation of TORC1. Here, we present the crystal structure of Gtr1p(GTP)-Gtr2p(GDP), the active yeast Rag GTPase heterodimer. The structure reveals that GTP-to-GDP conversion on Gtr2p results in a large conformational transition of this subunit, including a large scale rearrangement of a long segment whose corresponding region in RagA is involved in binding to Raptor. In addition, the two GTPase domains of the heterodimer are brought to contact with each other, but without causing any conformational change of the Gtr1p subunit. These features explain how the nucleotide-bound statuses of the two GTPases subunits switch the Raptor binding affinity on and off.
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The dramatic structural rearrangement in RagC switch I is reminiscent of the Gtr1GTP-Gtr2GDP structure, in which GDP-bound Gtr2 displays an extremely similar switch I conformation.
“This dramatic structural rearrangement is reminiscent of the Gtr1GTP-Gtr2GDP structure, in which GDP-bound Gtr2 displays an extremely similar switch I conformation (Jeong et al., 2012).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Jeong et al., 2012
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Lysosomal catch-and-release controls mTORC1
Hosios, A. M., & Manning, B. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0188-y · Cited by 8 · see citing works
Amino Acid Sensing: Architecture of mTORC1 on the Lysosome Surface
Peng, W., & Jewell, J. L. (2020) · Current Biology · doi:10.1016/j.cub.2019.11.087 · Cited by 5 · see citing works
Structures and Functions of the Human GATOR1 Complex
Ivanova, I., & Shen, K. (2024) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-031-58843-3_12 · Cited by 4 · see citing works
Egri, S. B., & Shen, K. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100861 · Cited by 4 · see citing works
“(2021) 297(1) 100861 different nucleotide-loading states (9, 10), as these two highresolution structures presented the clearest atomic details of the dramatic conformational changes of the Switch I region upon binding to GTP versus GDP (Fig.”
BackgroundTettoni, S. D., Egri, S. B., Doxsey, D. D., Veinotte, K., Ouch, C., Chang, J.-Y., Song, K., Chen, X., & Shen, K. (2023) · Structure · doi:10.1016/j.str.2023.06.012 · Cited by 3 · see citing works
The yoga of Rag GTPases: Dynamic structural poses confer amino acid sensing by mTORC1
Fingar, D. C. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101103 · Cited by 1 · see citing works
“The crystal structure of Rag heterodimers from budding yeast bound to GDP or GTP provided important structural information regarding how guanine nucleotide binding controls Rag architecture (9, 10).”
BackgroundA New Crosslinking Assay to Study Guanine Nucleotide Binding in the Gtr Heterodimer of S. cerevisiae
Doxsey, D. D., Veinotte, K., & Shen, K. (2022) · Small GTPases · doi:10.1080/21541248.2022.2141019 · Cited by 1 · see citing works
Exonuclease Xrn1 regulates TORC1 signaling in response to SAM availabilityPreprint
McGinnis, M. M., Sutter, B. M., Jahangiri, S., & Tu, B. P. (2023) · doi:10.7554/elife.91984.1 · Cited by 1 · see citing works
Exonuclease Xrn1 regulates TORC1 signaling in response to SAM availabilityPreprint
McGinnis, M. M., Sutter, B. M., Jahangiri, S., & Tu, B. P. (2023) · doi:10.7554/elife.91984 · Cited by 1 · see citing works
Workman, J. J. (2016) · doi:10.21007/etd.cghs.2016.0415
“These events coordinate the active nucleotide configuration of the Rag GTPases, with GTP-bound RagA/B and GDP-bound RagC/D [127].”
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Structural basis for FLCN RagC GAP activation in TFEB substrate-selective mTORC1 regulationPreprint
Jansen, R. M., Peruzzo, R., Fromm, S. A., Yokom, A. L., Zoncu, R., & Hurley, J. H. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.28.498039
Schoonover, M. G., Chilson, E. C., & Strome, E. D. (2022) · PubMed Central · doi:10.17912/micropub.biology.000685
“…via the Nitrogen Catabolite Repression (NCR) pathway in response to the quality of nitrogen sources and a potential feedback loop by TORC1 downstream effectors, Npr1p and Par32p, for quantity of nitrogen sources (Binda et al. 2009; Jeong et al. 2012; Sekiguchi et al. 2014; Li et al. 2017).”
BackgroundExonuclease Xrn1 regulates TORC1 signaling in response to SAM availabilityPreprint
McGinnis, M. M., Sutter, B. M., Jahangiri, S., & Tu, B. P. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.28.559955
Global conformation of the Rag GTPase heterodimer governs eukaryotic amino acid sensing
Doxsey, D. D., & Shen, K. (2025) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2517050122
“When a GDP molecule binds, Switch I relaxes and extends toward the CRD ( 29 ).”
Influential
- Authors
- Jeong, J.-H., Lee, K.-H., Kim, Y.-M., Kim, D.-H., Oh, B.-H., & Kim, Y.-G.
- Affiliations
- Pohang University of Science and Technology (KR)
- Korea Advanced Institute of Science and Technology (KR)
- University of Minnesota (US)
- Corresponding author
- Kim, Yeon-Gil
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 287
- Issue
- 35
- Pages
- 29648-29653
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3436135
- OpenAlex
- W1992987381
- Cited by
- 68
- References
- 20
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 8 · 2021: 3 · 2020: 5 · 2019: 8 · 2018: 7 · 2017: 10 · 2016: 5 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 2
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Research Foundation
- National Research Foundation of Korea (K20815000001)
- Ministry of Education, Science and Technology (2011-0007201)
- Ministry of Land, Transport and Maritime Affairs
- National Institutes of Health (DK072004)
- National Institute of General Medical Sciences (R01GM097057)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072004, DK072004, R56DK072004, DK083474, R56DK083474)
- 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 › Biochemical and Molecular Research
- Keywords
- Rag GTPases, raga, GTPase domain, amino acid signaling, Saccharomyces cerevisiae
- MeSH terms
- Guanosine Diphosphate, Guanosine Triphosphate, Multienzyme Complexes, Protein Binding, Saccharomyces cerevisiae, Crystallography, X-Ray, Monomeric GTP-Binding Proteins, Protein Structure, Quaternary, Saccharomyces cerevisiae Proteins
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