Ragulator

Pathway/Complex · 10 studies in the Atlas · also known as LAMTOR, LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4, LAMTOR5

Lysosome-anchored scaffold that recruits the Rag GTPases and positions mTORC1 on the lysosomal surface for activation.

The bolt holding the taxi to the membrane. A scaffold anchored to the lysosome that recruits the Rag GTPases and holds mTORC1 in position on the lysosome's surface so it can be switched on there.

First reported as a RagA/B GEF (BAR2012); later work places its exchange activity on RagC, with SLC38A9 loading RagA with GTP. The tethering role is the better-established one; LAMTOR1 lipidation anchors the whole assembly.

TL;DR. Ragulator appears in 10 curated studies in Oliver's mTOR Atlas: 10 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 3 interactions in the curated pathway model.

In the pathway model

3 interactions in the curated mTOR pathway model (2 acting from Ragulator, 1 acting on it). Each row is a claim with the evidence behind it; the evidence code is the kind of study, not its quality.

Interaction	Mechanism	Evidence	Studies
Ragulator activates Rag GTPases mechanism: scaffolding · this link in full · on the map table	Ragulator anchors the Rag proteins to the lysosome and also helps flip them into their "on" shape, together with a second protein, SLC38A9. Both jobs are shown in biochemical experiments.Ragulator does two jobs on the Rags. It tethers the Rag heterodimer to the lysosomal surface, and it acts as an unusual exchange factor: first reported as a GEF for RagA/B (BAR2012), its exchange activity was later placed on RagC, where releasing GTP unlocks the inactive state (SHE2018B). Loading RagA with GTP is done by arginine-bound SLC38A9 (see SLC38A9-RAG). Holds under: Human cells, Drosophila and purified recombinant proteins (BAR2012, SAN2010, SHE2018B). The exchange activity was first assigned to RagA/B and later to RagC, so the exact step is still being refined. Whole-animal and human relevance are not tested here. plausible in people, not shown directly · settled in the literature	M	BAR2012, SAN2010, SHE2018B
Ragulator inhibits cGAS-STING pathway mechanism: degradation · this link in full · on the map table	Lamtor5 belongs to Ragulator, the lysosome complex that switches mTORC1 on, but this link does not run through mTORC1 as far as the source shows. Lamtor5 grabs the inflammation sensor cGAS and sends it for disposal. When Lamtor5 falls with age in immune cells called macrophages, cGAS builds up and drives inflammation that spreads to neighbouring cells; in mice, moving such macrophages into young animals sped up their ageing. This is one mouse study, so it is not known whether the same happens in people, or whether mTORC1 plays any part.Lamtor5 binds cGAS directly and routes it for degradation through the ESCRT machinery, so the Ragulator subunit acts as a physical brake on the sensor itself. Age-related decline of Lamtor5 in macrophages leaves cGAS stabilised, and that is sufficient to unleash cGAS-mediated paracrine inflammatory signalling: transferring Lamtor5-deficient macrophages accelerates ageing in young mice, while restoring young macrophages, clearing senescent cells, or applying a small peptide that blocks the Lamtor5/cGAS interface alleviates the phenotype in aged mice. Holds under: One mouse study (LV2026), A - animal, and no human data for this link. The abstract reports no mTORC1 or mTORC2 measurement for the cGAS step, so whether mTORC1 signalling contributes at all is untested here rather than established. Macrophage-specific: the conditional knockout is myeloid, and the ageing phenotypes are read out at the organismal level, which is a long inferential chain from one protein interaction. not tested in people · emerging, few independent studies	A	LV2026
v-ATPase required-for Ragulator mechanism: binding · this link in full · on the map table	The lysosome's acid pump senses amino acids from the inside and passes that information out to Ragulator, which passes it on to the Rag proteins.The lysosome's proton pump talks to Ragulator from the inside out: amino acids inside the lysosome change v-ATPase, which changes Ragulator, which changes the Rags. Holds under: The 'inside-out' model requires amino acids to accumulate inside the lysosome first; how they get there for every amino acid is not fully mapped. plausible in people, not shown directly · emerging, few independent studies	M	ZON2011, BAR2012

Evidence at a glance

Evidence	What it means	Studies
M	Molecular — cells, biochemistry, structure	10

No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.

Studies

Year	Evidence	Study
2026	M	Structure and function of TM6SF1 reveals role in mTORC1 signaling HON2026 Cryo-EM structure of TM6SF1 identifies it as a lysosomal cholesterol-binding protein that directly engages LAMTOR1 (Ragulator) to regulate mTORC1 signaling in a cholesterol-dependent manner.
2025	M	Structural basis for mTORC1 activation on the lysosomal membrane CUI2025 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.
2023	M	Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex CUI2023 First structural view of how mTORC1 actually reaches TFEB to phosphorylate it: two full Rag-Ragulator complexes present a single TFEB molecule to the mTOR active site, one in the normal Raptor-docking arrangement and a second, non-canonical one that grips TFEB's own first helix. Mutating that grip point drives TFEB straight into the nucleus (turning on autophagy/lysosome genes) without disturbing where mTORC1 itself sits. Explains, at the level of atoms, why TFEB phosphorylation needs the tumour suppressor FLCN and the GDP-loaded state of RagC in a way the authors report for no other mTORC1 substrate. Boundary: cryo-EM of a complex reconstituted from purified human proteins — a static structural snapshot, not a live cell or a real-time measurement.
2022	M	A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids GOL2022 The four mammalian Rag GTPase paralogues are not functionally interchangeable: RagC/D determines substrate specificity (RagD favors TFEB/TFE3 phosphorylation via tighter LAMTOR binding), while RagA/B determines the response to amino acid withdrawal (RagB-expressing cells keep mTORC1 lysosomal and active even upon starvation). Author correction issued 2023 (PMID 36536178, no change to conclusions).
2019	M	Structural basis for the docking of mTORC1 on the lysosomal surface ROG2019 3.2-angstrom cryo-EM structure of Raptor bound to Rag-Ragulator, showing how Raptor reads out the nutrient-dependent nucleotide state of the Rag GTPases: one part of Raptor senses RagA's nucleotide state, a separate 'claw' senses RagC's, and both have to be in the correct nutrient-signalling combination before Raptor is allowed to dock. Mutating the contact points blocks mTORC1 from reaching the lysosome and inhibits its signalling, which is the functional evidence behind the structural claim. Combined with a separate structure of mTORC1 bound to its activator Rheb, the paper builds a model of the complete, active mTORC1 sitting on the lysosome. Boundary: cryo-EM of a complex reconstituted from purified human proteins, not a live-cell measurement.
2018	M	Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms SHE2018B Ragulator and SLC38A9 each act as an unusual guanine-nucleotide exchange factor on the Rag heterodimer, and together they push it into its active state. Ragulator triggers GTP release from RagC, which unlocks the inactive configuration; arginine-bound SLC38A9 converts RagA from the GDP- to the GTP-loaded state. Boundary: purified proteins and cultured human cells. This is the biochemistry of the switch, not a measurement in tissue.
2017	M	Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex SUX2017 Hybrid structural model of the RagA/C-Ragulator mTORC1 activation complex.
2012	M	MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB MAR2012 Showed mTORC1-dependent TFEB Ser211 phosphorylation: mTORC1 (docked at the lysosome via Ragulator) phosphorylates TFEB on Ser211, which traps it in the cytosol via 14-3-3 proteins. Inhibit mTORC1 and TFEB rushes to the nucleus to switch on autophagy - explaining how mTORC1 controls recycling at the level of gene transcription.
2011	M	mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase ZON2011 Showed amino acid sensing starts INSIDE the lysosome: amino acids accumulate in the lumen and the v-ATPase relays that signal outward ('inside-out') to Ragulator-Rag. A surprising twist on where the cell measures its nutrient status.
2010	M	Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids SAN2010 Established WHERE mTORC1 gets switched on: the lysosome surface. Identified Ragulator as the lysosomal dock that recruits the Rag GTPases and drags mTORC1 to the membrane where its activator Rheb lives. Amino acids work by controlling this translocation.

Related entities

mTORC1 9 Rag GTPases 8 TFEB 4 Lysosome 3 Raptor 3 Rheb 3 v-ATPase 1 Arginine 1 SLC38A9 1 Autophagy 1 FLCN / FNIP1/2 1

Cite this page

ShowHide

Barton, O. (2026). Ragulator [Entity page]. In Oliver's mTOR Atlas [Data set]. https://mtor-atlas.org/complex/ragulator/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_complex_ragulator,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}: Ragulator},
  howpublished = {Entity page in a data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/complex/ragulator/},
  doi          = {10.5281/zenodo.22059963}
}

Was this page useful?