Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex
What this study shows
Cryo-EM structure of human GATOR2 bound to the arginine-free state of CASTOR1 (3.89 A overall, 3.02-3.72 A after local refinement). Two MIOS beta-propellers of the GATOR2 cage each grip one subunit of the CASTOR1 dimer through a negatively charged surface far from the arginine pocket. Comparing with earlier CASTOR1 structures, arginine binding makes a loop in CASTOR1 fold over that surface, so CASTOR1 can no longer hold GATOR2 and the signal passes on to mTORC1. In HEK293T cells, point mutations on either side of the interface weakened the CASTOR1-GATOR2 interaction, and CASTOR1 mutants could not restore arginine-dependent control of S6K1 phosphorylation. Boundary: purified human proteins, an arginine-free state mimicked by a mutant CASTOR1, and HEK293T cells — a structural and biochemical model, not a measurement in animals or people.
At a glance
| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human GATOR2 with an arginine-free (apo-locked) CASTOR1 mutant (cryo-EM, purified proteins); validation by mutants in HEK293T cells) 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 GATOR2 with an arginine-free (apo-locked) CASTOR1 mutant (cryo-EM, purified proteins); validation by mutants in HEK293T cells |
| Journal | Nature Structural & Molecular Biology |
| Year | 2025 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1038/s41594-025-01635-0 · PMID 40715445 · Free full text (PMC12477443) |
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 | None (structural study); CASTOR1 and MIOS interface point mutants for validation |
| Target | CASTOR1-GATOR2 interface (MIOS beta-propellers) |
| Model | Human proteins (cryo-EM); HEK293T cells (mutant validation) |
| Effect | Arginine binding closes the MIOS-binding surface of CASTOR1, releasing it from GATOR2 |
In the Atlas
Related topics
Links in the pathway map
- Supports Arginine inhibits CASTOR1
- Supports CASTOR1 inhibits GATOR2
More studies on this topic
- The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway (2016)
- Structure of the nutrient-sensing hub GATOR2 (2022)
- Structural basis for the dynamic regulation of mTORC1 by amino acids (2025)
- A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1 (2013)
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