An Autoinhibited Noncanonical Mechanism of GTP Hydrolysis by Rheb Maintains mTORC1 Homeostasis
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Rheb, an activator of mammalian target of rapamycin (mTOR), displays low intrinsic GTPase activity favoring the biologically activated, GTP-bound state. We identified a Rheb mutation (Y35A) that increases its intrinsic nucleotide hydrolysis activity ∼10-fold, and solved structures of both its active and inactive forms, revealing an unexpected mechanism of GTP hydrolysis involving Asp65 in switch II and Thr38 in switch I. In the wild-type protein this noncanonical mechanism is markedly inhibited by Tyr35, which constrains the active site conformation, restricting the access of the catalytic Asp65 to the nucleotide-binding pocket. Rheb Y35A mimics the enthalpic and entropic changes associated with GTP hydrolysis elicited by the GTPase-activating protein (GAP) TSC2, and is insensitive to further TSC2 stimulation. Overexpression of Rheb Y35A impaired the regulation of mTORC1 signaling by growth factor availability. We demonstrate that the opposing functions of Tyr35 in the intrinsic and GAP-stimulated GTP catalysis are critical for optimal mTORC1 regulation.
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Y35 prevents GTP dissociation by closing over the nucleotide binding pocket, coordinating the phosphates more tightly than in Ras and Rap.
“Y35 also prevents GTP dissociation by closing over the nucleotide binding pocket (Fig. 6C), coordinating the phosphates more tightly than in Ras and Rap (Mazhab-Jafari et al., 2012).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Mazhab-Jafari et al., 2012
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“Rheb is ubiquitously expressed in humans and is an activator in the mammalian target of rapamycin complex 1 (mTORC1) pathway; the activation of mTORC1, a serine/threonine kinase, leads to phosphorylation cascades that result in cell growth and proliferation [11].”
BackgroundHeard, J. J., & Tamanoi, F. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6438-9_101614-1
Heard, J. J., & Tamanoi, F. (2017) · Springer eBooks · doi:10.1007/978-3-319-67199-4_101614
Unraveling the Binding Mode of TSC2–Rheb through Protein Docking and Simulations
Pape, B. F., Parate, S., Eriksson, L. A., & Jha, V. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00562
- Authors
- Mazhab-Jafari, M. T., Marshall, C. B., Ishiyama, N., Ho, J., Di Palma, V., Stambolic, V., & Ikura, M.
- Affiliations
- University Health Network (CA)
- Corresponding author
- Stambolic, Vuk
- Ikura, Mitsuhiko
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 20
- Issue
- 9
- Pages
- 1528-1539
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2150953043
- Cited by
- 37
- References
- 49
- Citations by year
- 2025: 6 · 2024: 2 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 6 · 2016: 3 · 2015: 2 · 2014: 6 · 2013: 1
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- 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 › Cell Biology › Cellular transport and secretion
- Keywords
- Rheb, GTP hydrolysis, mTORC1, autoinhibition, switch II, switch I, TSC2, GTPase-activating protein, nucleotide-binding pocket, protein structure, growth factor signaling
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Mechanistic Target of Rapamycin Complex 1, Animals, Enzyme Activation, Guanosine Triphosphate, HeLa Cells, Homeostasis, Humans, Hydrogen Bonding, Hydrolysis, Kinetics, Models, Molecular, Neuropeptides, Protein Binding, Proteins, Thermodynamics, Mutagenesis, Site-Directed, Crystallography, X-Ray, Amino Acid Substitution, Catalytic Domain, Monomeric GTP-Binding Proteins, Amino Acid Motifs, Ribosomal Protein S6 Kinases, 70-kDa, Multiprotein Complexes, Mice, HEK293 Cells, TOR Serine-Threonine Kinases
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