9LVK

Cryo-EM structure of CASTOR1 bound human GATOR2 complex

Summary for 9LVK

• Entry DOI: 10.2210/pdb9lvk/pdb
• EMDB information: 63421 63422
• Descriptor: GATOR2 complex protein MIOS, GATOR2 complex protein WDR24, GATOR2 complex protein WDR59, ... (7 entities in total)
• Functional Keywords: amino acid sensor, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 18
• Total formula weight: 1227291.47

Authors

Su, M.-Y. (deposition date: 2025-02-12, release date: 2025-08-13)

Primary citation

Su, M.Y.,Teng, F.,Wang, S.,Mai, X.,Zeng, H.,Li, J.,Song, X.,Wang, X.,Stjepanovic, G.
Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex.
Cell Rep, 44:116088-116088, 2025

PubMed Abstract: 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.

PubMed: 40742811
DOI: 10.1016/j.celrep.2025.116088

Experimental method

ELECTRON MICROSCOPY (3.59 Å)