EGOC inhibits TOROID polymerization by structurally activating TORC1
Open accessPublished version of a preprint
Abstract
Target of rapamycin complex 1 (TORC1) is a protein kinase controlling cell homeostasis and growth in response to nutrients and stresses. In Saccharomyces cerevisiae , glucose depletion triggers a redistribution of TORC1 from a dispersed localization over the vacuole surface into a large, inactive condensate called TOROID (TORC1 organized in inhibited domains). However, the mechanisms governing this transition have been unclear. Here, we show that acute depletion and repletion of EGO complex (EGOC) activity is sufficient to control TOROID distribution, independently of other nutrient-signaling pathways. The 3.9-Å-resolution structure of TORC1 from TOROID cryo-EM data together with interrogation of key interactions in vivo provide structural insights into TORC1-TORC1′ and TORC1-EGOC interaction interfaces. These data support a model in which glucose-dependent activation of EGOC triggers binding to TORC1 at an interface required for TOROID assembly, preventing TORC1 polymerization and promoting release of active TORC1.
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- Authors
- Prouteau, M., Bourgoint, C., Felix, J., Bonadei, L., Sadian, Y., Gabus, C., Savvides, S. N., Gutsche, I., Desfosses, A., & Loewith, R.
- Affiliations
- University of Geneva (CH)
- Ghent University (BE)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Prouteau, Manoël
- Loewith, Robbie
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2023-01-26
- Volume
- 30
- Issue
- 3
- Pages
- 273-285
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC10023571
- OpenAlex
- W4318071652
- Cited by
- 15
- References
- 3
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 4 · 2023: 3
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- European Molecular Biology Laboratory
- Infrastructures en Biologie Santé et Agronomie (ANR-17-EURE-0003, ANR-10-INBS-05-02)
- European Commission (ANR-17-EURE-0003, 789385, 647784, HORIZON2020)
- Agence Nationale de la Recherche (ANR-17-EURE-0003, ANR-10-INBS-05-02, ANR-10- INBS-05, ANR-17-EURE-, ANR-17, ANR-10, ANR-10-INBS-0005)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fondation pour la Recherche Médicale (ANR-17-EURE-0003, ANR-10-INBS-05-02)
- Vlaams Instituut voor Biotechnologie
- Centre National de la Recherche Scientifique
- Université de Genève
- French Infrastructure for Integrated Structural Biology (ANR-17-EURE-0003, ANR-10-INBS-05–02, ANR-10-INBS-0.5)
- Canton de Genève
- Vlaamse regering
- H2020 Marie Skłodowska-Curie Actions (ANR-17-EURE-0003, HORIZON2020)
- 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 › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- TORC1, toroids, glucose signaling, nutrient signaling, protein kinase activation, Saccharomyces cerevisiae, cryo-EM structure
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Glucose, Saccharomyces cerevisiae, Transcription Factors, Saccharomyces cerevisiae Proteins, Polymerization
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