Structural basis for mTORC1 activation on the lysosomal membrane
What this study shows
Resolves how mTORC1 flips from 'parked on the lysosome' to 'catalytically switched on'. Reconstituting the whole assembly on membranes from purified Rheb, Rag GTPases, Ragulator and mTORC1, cryo-EM shows the kinase reaches full activity only after two separate anchoring steps: Rag-Ragulator first pulls it to within about 100 angstroms of the membrane, then Rheb pulls it to within about 40 angstroms, and only when Raptor and mTOR itself also touch the membrane directly do the catalytic residues line up for full activity. Growth-factor input (via Rheb) and nutrient input (via the Rags) are shown converging on the same physical docking event rather than acting through separate switches. Boundary: reconstituted on synthetic membranes from purified components — a structural/biochemical model, not a measurement inside a living cell.
Abstract
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The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth factor (GF) and nutrient signals to stimulate anabolic processes connected to cell growth and inhibit catabolic processes such as autophagy. GF signalling through the tuberous sclerosis complex regulates the lysosomally localized small GTPase RAS homologue enriched in brain (RHEB). Direct binding of RHEB-GTP to the mTOR kinase subunit of mTORC1 allosterically activates the kinase by inducing a large-scale conformational change. Here we reconstituted mTORC1 activation on membranes by RHEB, RAGs and Ragulator.
Read the full abstract on PubMed →At a glance
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| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Cryo-EM structure (human proteins, reconstituted on membranes) + validation in inducible RAPTOR-KO MEFs) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Cryo-EM structure (human proteins, reconstituted on membranes) + validation in inducible RAPTOR-KO MEFs |
| Journal | Nature |
| Year | 2025 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1038/s41586-025-09545-3 · PMID 40963021 · Free full text (PMC12448111) |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
Pathway relations
Supports
Lysosome required-for mTORC1Strongest evidence: M (Molecular — cells, biochemistry, structure) · settled in the literature · Status: Proposed
plausible in people, not shown directly
Scoped to amino-acid-driven activation. Live BRET imaging in this corpus (BOU2020) resolves mTOR activity in the cytosol, at the lysosome, in the nucleus and near mitochondria, so mTOR signalling is measurably not one pool. This map draws…
Supports
Rag GTPases recruits mTORC1Strongest evidence: A (Animal model) · settled in the literature · Status: Proposed
plausible in people, not shown directly
Rag paralogues are not interchangeable: RagC/D sets substrate specificity downstream (RagD favors TFEB/TFE3 phosphorylation via tighter LAMTOR binding, while both Rags are involved for non-lysosomal substrates like S6K), and RagA/B sets…
Supports
Rheb activates mTORC1Strongest evidence: H (Human study) · settled in the literature · Status: Proposed
plausible in people, not shown directly
Cryo-EM structures, in vitro biochemistry, Drosophila and one mouse study (INOK2003, SAU2003, YAN2017, CUI2025, DEL2011) define how Rheb activates mTORC1 in reconstituted and cellular systems. Human tissue evidence is genetic and indirect:…
People in the Atlas
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Structural biologist who solved cryo-EM structures of the mTORC1–TFEB–Rag–Ragulator megacomplex and of mTORC1 switched on by RHEB and the Rags on a lipid membrane.
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Structural biologist who uses cryo-EM to show how protein machines assembled on membranes control autophagy and nutrient signalling. His lab solved structures of the Rag–Ragulator complex and of the whole mTORC1–TFEB–Rag–Ragulator assembly on the lysosome
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Lysosomal signalling and TFEB regulation
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mTORC1-TFEB lysosomal signalling
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Discovered that the transcription factor TFEB is a master switch for building lysosomes (SAR2009) and for autophagy. His lab was one of the groups that showed in 2012 that mTORC1 keeps TFEB out of the nucleus from the lysosome surface, and later (2020) that constitutive TFEB activation drives the kidney disease of Birt-Hogg-Dubé syndrome
Related studies
- M Structural basis for the docking of mTORC1 on the lysosomal surface
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SAN2010 · 2010 · Shares: Rag GTPases, mTORC1, Rheb, Ragulator
- M Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex
CUI2023 · 2023 · Shares: Raptor, Rag GTPases, mTORC1, Ragulator
- M A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids
GOL2022 · 2022 · Shares: Rag GTPases, mTORC1, Ragulator
- M Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex
SUX2017 · 2017 · Shares: Rag GTPases, mTORC1, Ragulator
More related studies
- M mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase
ZON2011 · 2011 · Shares: Rag GTPases, mTORC1, Ragulator
- M PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase
SAN2007 · 2007 · Shares: Raptor, mTORC1, Rheb
- M Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2
DEM2014 · 2014 · Shares: Rag GTPases, mTORC1, Rheb
- M Architecture of human Rag GTPase heterodimers and their complex with mTORC1
ANA2019 · 2019 · Shares: Raptor, Rag GTPases, mTORC1
- M Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms
SHE2018B · 2018 · Shares: Rag GTPases, Ragulator
- M Structure and function of TM6SF1 reveals role in mTORC1 signaling
HON2026 · 2026 · Shares: mTORC1, Ragulator
- M MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB
MAR2012 · 2012 · Shares: mTORC1, Ragulator
- A Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion
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Topics
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | Structural/biochemical reconstitution (cryo-EM, membrane-bound complex) |
| Target | mTORC1-Rheb-Rag-Ragulator activation complex on membranes |
| Model | Human proteins, cell-free reconstitution on synthetic membranes; validation in inducible RAPTOR-knockout mouse embryonic fibroblasts |
| Effect | Four-step model of mTORC1 recruitment and activation on the lysosomal membrane, integrating growth-factor (Rheb) and nutrient (Rag-Ragulator) signals into one docking/activation mechanism |
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