A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids
What this study shows
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).
Abstract
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Amino acid availability controls mTORC1 activity via a heterodimeric Rag GTPase complex that functions as a scaffold at the lysosomal surface, bringing together mTORC1 with its activators and effectors. Mammalian cells express four Rag proteins (RagA-D) that form dimers composed of RagA/B bound to RagC/D. Traditionally, the Rag paralogue pairs (RagA/B and RagC/D) are referred to as functionally redundant, with the four dimer combinations used interchangeably in most studies.
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: Human cells (genetically modified Rag-paralogue cell lines)) 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 | Human cells (genetically modified Rag-paralogue cell lines) |
| Journal | Nature Cell Biology |
| Year | 2022 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1038/s41556-022-00976-y · PMID 36097072 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
Pathway relations
Supports
mTORC1 inhibits TFEBStrongest evidence: M (Molecular — cells, biochemistry, structure) · settled in the literature · Status: Proposed
plausible in people, not shown directly
RagD specifically (more than RagC) promotes TFEB/TFE3 phosphorylation via tighter LAMTOR binding — GOL2022 shows this is paralogue-specific, not a generic Rag-dimer property.
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…
People in the Atlas
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First author of the 'Rag dimer code' study showing that the four Rag GTPase paralogues are not interchangeable: RagC/D sets substrate choice and RagA/B sets the response to amino acid withdrawal.
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Showed as a postdoc in Aurelio Teleman's lab that starvation and other stresses pull TSC2 to the lysosome to switch mTORC1 off. His group, at the Max Planck Institute for Biology of Ageing in Cologne from 2017 and at ERIBA in Groningen since 2025, studies how cells sense nutrients and stress through mTORC1 and how this changes with age
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Co-author on two Demetriades-lab studies of amino acid sensing by mTORC1: the Rag GTPase dimer code and the spatial split of mTORC1 signalling.
More: 2 other authors
No profile yet: Grützmacher N, Kümmel D
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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 | Cell lines engineered to express single Rag heterodimers; amino-acid withdrawal |
| Target | Rag GTPase paralogues (RagA/B, RagC/D), mTORC1 substrate selection, TFEB/TFE3 |
| Model | Human cell lines |
| Effect | RagD promotes phosphorylation of lysosomal substrates TFEB/TFE3 through tighter LAMTOR binding, while RagB-expressing cells keep mTORC1 lysosomal and active even during starvation. |
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