#1

https://www.nature.com/articles/s41586-025-09428-7

Here’s a structured breakdown of the uploaded paper “Structural basis for the dynamic regulation of mTORC1 by amino acids” (Nature, 2025):

Summary

  • Background
    mTORC1 is a central kinase complex regulating growth, metabolism, and aging, activated by amino acids via Rag GTPases and the GATOR supercomplex. GATOR2 is a key hub, interacting with nutrient sensors (Sestrins for leucine, CASTOR1 for arginine), but how amino acid binding leads to GATOR2 disengagement and mTORC1 activation was unclear.
  • Methods
    The authors engineered a single-chain GATOR2 (sc-GATOR2) to stabilize the complex for cryo-EM. They solved structures of:
    • Apo sc-GATOR2
    • sc-GATOR2 bound to Sestrin2 (leucine sensor)
    • sc-GATOR2 bound to CASTOR1 (arginine sensor) They also captured the previously elusive apo (leucine-free) Sestrin2 structure and performed biochemical assays, mutagenesis, and molecular dynamics.
  • Key Findings
    1. Distinct binding sites: Sestrin2 and CASTOR1 bind non-overlapping GATOR2 surfaces (WDR24–SEH1L for Sestrin2, MIOS brace for CASTOR1).
    2. Mechanism of nutrient sensing:
    • Leucine: induces an allosteric rearrangement in Sestrin2, repositioning residues (Arg338, Arg404) to clash with GATOR2, triggering dissociation.
    • Arginine: causes structural changes in CASTOR1 (helix α3 kink, loop β6–α3 repositioning) that clash with MIOS Arg137, releasing CASTOR1.
    1. Shared regulatory principle: Both sensors rigidify the flexible WDR24 β-propeller, a domain required for mTORC1 activation, thereby antagonizing GATOR2 function.
    2. Physiological implication: GATOR2 variants engineered to resist either Sestrin- or CASTOR-mediated inhibition enable dissection of leucine vs arginine sensing in vivo.

Novelty

  • First high-resolution cryo-EM structures of GATOR2 bound to its nutrient sensors (Sestrin2, CASTOR1).
  • First structure of apo (leucine-free) Sestrin2, long sought but previously unstable for purification.
  • Discovery that ligand binding does not require prior dissociation from GATOR2; instead, amino acids trigger allosteric structural cascades within the sensors that create steric clashes, forcing release.
  • Identification of WDR24 β-propeller dynamics as a central regulatory element modulated by both sensors, providing a unifying mechanism of inhibition.
  • Provision of GATOR2 sensor-resistant mutants as new tools for in vivo dissection of nutrient sensing.

Critique

Strengths

  • Elegant use of engineered single-chain GATOR2 to overcome instability and allow structural resolution.
  • Clear mechanistic explanation of how leucine and arginine sensors disengage from GATOR2.
  • Integrates structural biology with mutagenesis and functional assays for validation.
  • Provides conceptual advance by highlighting the dynamic WDR24 β-propeller as the key “switch” in mTORC1 activation.

Limitations

  • Structures capture bound states, but the free apo Sestrin2 structure (not in complex with GATOR2) remains unresolved, leaving open whether some features are GATOR2-induced.
  • In vitro biochemistry dominates; while sensor-resistant GATOR2 mutants are promising, physiological in vivo data are not yet included.
  • The role of other GATOR regulators (e.g., KICSTOR, SAMTOR) remains unresolved.
  • Some conclusions (e.g., proposed evolutionary adaptation of nutrient sensors) are speculative without evolutionary/functional testing.
  • Dynamic aspects (ligand exchange rates, reassociation kinetics) are inferred rather than directly measured.

:white_check_mark: Overall: This is a landmark mechanistic paper in mTORC1 nutrient sensing, solving long-standing structural questions (especially apo Sestrin2) and offering a unifying framework for how amino acid sensors regulate GATOR2. However, it leaves the physiological integration and dynamics of the system still open for future work.

My comment:

i think we knew leucine, but also arginine?