GATOR2
Positive arm that inhibits GATOR1; the target through which amino acid sensors (Sestrin2, CASTOR1) relay their signal to mTORC1.
A brake on the brake. A relay switch that reactivates mTORC1. Amino-acid sensors like Sestrin2 and CASTOR1 work by inhibiting it (when nutrients are scarce) or releasing it (when nutrients return), and it in turn keeps GATOR1 - mTORC1's main brake - in check.
Structures (Valenstein 2022) resolved the cage-like architecture and the Sestrin2/CASTOR1 binding surfaces; how it inhibits GATOR1 catalytically is still argued.
TL;DR. GATOR2 appears in 4 curated studies in Oliver's mTOR Atlas: 4 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
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| GATOR2 inhibits GATOR1 mechanism: binding · this link in full · on the map table | Everyone agrees GATOR2 holds GATOR1 back when amino acids are around. Exactly how it does it is not settled by the work this Atlas holds, and the gap is left visible on purpose. Released GATOR2 suppresses GATOR1 - a double negative. Two brakes in series is why the sensors can flip mTORC1 on so sharply. Released GATOR2 suppresses GATOR1 - a double negative. Two brakes in series is why the sensors can flip mTORC1 on so sharply. Holds under: The epistasis is solid. VAL2022 resolved GATOR2's architecture by cryo-EM - a 1.1 MDa cage - and mapped where the sensors dock, but exactly how GATOR2 suppresses GATOR1's GAP activity is still not settled. plausible in people, not shown directly · emerging, few independent studies | M | BAR2013, PAR2014, VAL2022 |
| CASTOR1 inhibits GATOR2 mechanism: binding · this link in full · on the map table | Without arginine, CASTOR1 holds onto GATOR2 and keeps the pathway switched off. Arginine-free CASTOR1 binds GATOR2 and inhibits it, so the pathway stays off until arginine is available. Arginine-free CASTOR1 binds GATOR2 and inhibits it, so the pathway stays off until arginine is available. Holds under: Human cell biochemistry and structure (CHA2016, SAX2016). The binding is shown in cells; there is no whole-animal or human test in the cited studies. plausible in people, not shown directly · settled in the literature | M | CHA2016, SAX2016 |
| Sestrin2 inhibits GATOR2 mechanism: binding · this link in full · on the map table | When there's no leucine, Sestrin2 grabs onto GATOR2 and holds the whole growth pathway shut. When leucine is scarce, free Sestrin2 clamps onto GATOR2 and blocks it, keeping the whole pathway switched off. When leucine is scarce, free Sestrin2 clamps onto GATOR2 and blocks it, keeping the whole pathway switched off. Holds under: Mammalian cell studies (CHA2014, PAR2014, WOL2015). Shows leucine sensing in cultured cells; the importance of this sensor in whole animals and people is not tested by these studies. plausible in people, not shown directly · settled in the literature | M | CHA2014, PAR2014, WOL2015 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| M | Molecular — cells, biochemistry, structure | 4 |
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 | "Trojan" Methionine Probe Reveals PKM2 as a Methionine-Sensing Protein in the mTORC1 Pathway SANG2026 Identifies PKM2 as a direct methionine sensor for mTORC1. A photoaffinity methionine analogue plus chemoproteomics showed that PKM2 binds free methionine through a distinct recognition pocket — independently of its glycolytic enzyme activity — and transduces methionine availability to mTORC1 via the GATOR2 complex. Complements SAMTOR (GU2017), which reads the methionine metabolite SAM rather than methionine itself, and suggests a route to a pharmacological "methionine pseudostarvation" state. |
| 2022 | M | Structure of the nutrient-sensing hub GATOR2 VAL2022 Cryo-EM structure of human GATOR2: a 1.1 MDa, two-fold symmetric cage built on an octagonal scaffold decorated with eight pairs of WD40 beta-propellers, and a map of where Sestrin2 and CASTOR1 dock. It substantially advances the GATOR2 side of the sensor module, though how GATOR2 inhibits GATOR1 is still not fully settled. |
| 2016 | M | The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway CHA2016 Identified CASTOR1 as the direct arginine sensor: when arginine binds CASTOR1, it lets go of GATOR2, switching mTORC1 on. Together with Sestrin2 (leucine) this built the picture of mTORC1 as a cell that literally tastes individual amino acids. |
| 2013 | M | A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1 BAR2013 Found the OFF switch for amino acid signaling: the GATOR1 complex is a GAP that shuts the Rag GTPases (and thus mTORC1) down when amino acids run low, while GATOR2 opposes it. GATOR1 genes are mutated in cancers, making those tumors 'blind' to starvation and hypersensitive to rapamycin. |
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