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TitleCryo-EM structures of amino acid sensors bound to the human GATOR2 complex.
Journal, issue, pagesCell Rep, Vol. 44, Issue 8, Page 116088, Year 2025
Publish dateJul 29, 2025
AuthorsMing-Yuan Su / Fei Teng / Shan Wang / Xinyi Mai / Huan Zeng / Juan Li / Xiaoxiao Song / Xi Wang / Goran Stjepanovic /
PubMed AbstractMammalian cells regulate growth by integrating environmental cues through the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. The human GATOR2 complex, comprising WDR59, WDR24, ...Mammalian cells regulate growth by integrating environmental cues through the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. The human GATOR2 complex, comprising WDR59, WDR24, Mios, Sec13, and Seh1l, is key to mTORC1 regulation. Under amino acid deprivation, GATOR2 is inhibited through interactions with cytosolic leucine sensor Sestrin2 and arginine sensor cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1). Amino acid abundance relieves this inhibition, allowing GATOR2 to antagonize the repressor GATOR1. Despite its importance, GATOR2's inhibition mechanisms were unclear. Here, we present cryo-electron microscopy (cryo-EM) structures of GATOR2 in three inhibitory states: CASTOR1 bound, Sestrin2 bound, and dual bound. CASTOR1 engages the Mios WD40 β-propellers, while Sestrin2 interacts with the WDR24-Seh1l subcomplex, inducing conformational movements. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) reveals dynamic motions in apo-GATOR2 and its complexes with amino acid sensors, as well as the effects of amino acid supplementation. These findings unravel the interactions between GATOR2 and amino acid sensors, providing a perspective on the regulation of the mTORC1 pathway by nutrient-sensing machinery.
External linksCell Rep / PubMed:40742811
MethodsEM (single particle)
Resolution3.41 - 3.82 Å
Structure data

63421

9lvj

EMDB-63421, PDB-9lvj:
Cryo-EM structure of Sestrin2 bound human GATOR2 complex
Method: EM (single particle) / Resolution: 3.82 Å

63422

9lvk

EMDB-63422, PDB-9lvk:
Cryo-EM structure of CASTOR1 bound human GATOR2 complex
Method: EM (single particle) / Resolution: 3.59 Å

63442

9lwf

EMDB-63442, PDB-9lwf:
Cryo-EM structure of dual sensor bound GATOR2 complex
Method: EM (single particle) / Resolution: 3.41 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Amino acid sensor / STRUCTURAL PROTEIN

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