Structural basis for the dynamic regulation of mTORC1 by amino acids
What this study shows
Cryo-EM structures of a stabilised GATOR2 cage bound to the leucine sensor Sestrin2 or the arginine sensor CASTOR1, plus a structure of leucine-free (apo) Sestrin2, a form that had not been resolved before. The two sensors sit on separate, non-overlapping sites on GATOR2, and mutating those sites selectively blunts mTORC1's response to one amino acid but not the other. When leucine or arginine binds, each sensor changes shape and lets go of GATOR2; while a sensor is attached it holds the mobile WDR24 beta-propeller of GATOR2 in place, a domain needed for nutrient-dependent mTORC1 activation. This shows physically how 'amino acid present' is passed to GATOR2. Boundary: purified human proteins and HEK293T cells — a structural and biochemical model, not a measurement in animals or people. The authors note that some features seen in the Sestrin2 complex may be induced by GATOR2 binding rather than by loss of leucine.
At a glance
| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human GATOR2 with Sestrin2 or CASTOR1 (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 Sestrin2 or CASTOR1 (cryo-EM, purified proteins); validation by mutants in HEK293T cells |
| Journal | Nature |
| Year | 2025 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1038/s41586-025-09428-7 · PMID 40836086 · Free full text (PMC12507694) |
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); sensor-site mutants for validation |
| Target | GATOR2 complex with Sestrin2 and CASTOR1 binding sites; WDR24 beta-propeller |
| Model | Human proteins (cryo-EM); HEK293T cells (mutant validation) |
| Effect | Sestrin2 and CASTOR1 occupy distinct sites on GATOR2 and restrict its WDR24 propeller; amino-acid binding changes each sensor's shape and releases it from GATOR2 |
In the Atlas
Related topics
Links in the pathway map
- Supports Arginine inhibits CASTOR1
- Supports CASTOR1 inhibits GATOR2
- Supports Leucine inhibits Sestrin2
- Supports Sestrin2 inhibits GATOR2
More studies on this topic
- Structure of the nutrient-sensing hub GATOR2 (2022)
- The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway (2016)
- Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex (2025)
- The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway (2017)
Thank you. Your answer was counted anonymously.