Structural basis for the assembly of the Ragulator-Rag GTPase complex
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The mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in regulating cell growth and metabolism by responding to cellular nutrient conditions. The activity of mTORC1 is controlled by Rag GTPases, which are anchored to lysosomes via Ragulator, a pentameric protein complex consisting of membrane-anchored p18/LAMTOR1 and two roadblock heterodimers. Here we report the crystal structure of Ragulator in complex with the roadblock domains of RagA-C, which helps to elucidate the molecular basis for the regulation of Rag GTPases. In the structure, p18 wraps around the three pairs of roadblock heterodimers to tandemly assemble them onto lysosomes. Cellular and in vitro analyses further demonstrate that p18 is required for Ragulator-Rag GTPase assembly and amino acid-dependent activation of mTORC1. These results establish p18 as a critical organizing scaffold for the Ragulator-Rag GTPase complex, which may provide a platform for nutrient sensing on lysosomes.
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The heptameric Ragulator-Rag complex structure showed Rag C-terminal roadblock domains binding to the LAMTOR2-LAMTOR3 heterodimer, building a tower of three roadblock domain-mediated heterodimers tied together by the extended LAMTOR1 subunit, and presenting the GTPase domains for interaction with RAPTOR.
“The heptameric Ragulator-Rag complex structure showed Rag C-terminal roadblock domains binding to the LAMTOR2-LAMTOR3 heterodimer (de Araujo et al., 2017; Su et al., 2017; Yonehara et al., 2017) (Fig. 4B), thus building a tower of three roadblock domain-mediated heterodimers tied together by the extended LAMTOR1 subunit, and presenting the GTPase domains for interaction with RAPTOR.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Yonehara et al., 2017
When the Rag heterodimer binds Ragulator, the N-terminal portion of LAMTOR1 encompassing residues 47-64 is resolved, forming an α-helix which packs against the RagC roadblock domain, whereas in the Ragulator complex alone this region of LAMTOR1 was disordered.
“It is important to note that when the Rag heterodimer binds Ragulator, the N-terminal portion of LAMTOR1 encompassing residues 47-64 is resolved, forming an α-helix which packs against the RagC roadblock domain, whereas in the Ragulator complex alone this region of LAMTOR1 was disordered (de Araujo et al., 2017; Yonehara et al., 2017).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Yonehara et al., 2017
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- Authors
- Yonehara, R., Nada, S., Nakai, T., Nakai, M., Kitamura, A., Ogawa, A., Nakatsumi, H., Nakayama, K. I., Li, S., Standley, D. M., Yamashita, E., Nakagawa, A., & Okada, M.
- Affiliations
- Institute for Protein Research, The University of Osaka (JP)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Kyushu University (JP)
- Corresponding author
- Nakagawa, Atsushi
- Okada, Masato
- ORCID
- Venue
- Nature Communications
- Published
- 2017-11-20
- Volume
- 8
- Issue
- 1
- Pages
- 1625-1625
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5696360
- OpenAlex
- W2768374432
- Cited by
- 75
- References
- 53
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 11 · 2021: 8 · 2020: 9 · 2019: 11 · 2018: 8
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology (26114006)
- Japan Society for the Promotion of Science (17K19596, 17H06004, 15H04296, 26114006, 25221303, 26640078)
- Institute for Protein Research, Osaka University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Rag GTPases, mTORC1, lysosomes, amino acid signaling, nutrient sensing, protein complex formation, crystal structure, cell growth regulation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Humans, Lysosomes, Protein Binding, Monomeric GTP-Binding Proteins, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Protein Multimerization
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