Structural basis for mTORC1 activation on the lysosomal membrane

Cui Z, Esposito A, Napolitano G, Ballabio A, Hurley JH · 2025 · Nature · Atlas ID CUI2025

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

ShowHide

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

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)) 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)
Journal	Nature
Year	2025
Peer reviewed	Yes
Record last updated	2026-09-23
Source	DOI 10.1038/s41586-025-09545-3 · PMID 40963021 · Free full text (PMC12448111)

Extracted findings

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
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

In the Atlas

Cite this paper

ShowHide

Cui, Z., Esposito, A., Napolitano, G., Ballabio, A., & Hurley, J. H. (2025). Structural basis for mTORC1 activation on the lysosomal membrane. Nature. https://doi.org/10.1038/s41586-025-09545-3

@article{CUI2025,
  author       = {Cui, Z. and Esposito, A. and Napolitano, G. and Ballabio, A. and Hurley, J. H.},
  title        = {{Structural basis for mTORC1 activation on the lysosomal membrane}},
  journal      = {Nature},
  year         = {2025},
  doi          = {10.1038/s41586-025-09545-3},
  note         = {PMID: 40963021},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record CUI2025) [Data set]. https://mtor-atlas.org/study/CUI2025/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_CUI2025,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record CUI2025},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/CUI2025/},
  doi          = {10.5281/zenodo.22059963}
}