Structure of the nutrient-sensing hub GATOR2

The mechanistic target of rapamycin complex 1 (mTORC1) controls growth by regulating anabolic and catabolic processes in response to environmental cues, including nutrients(1,2). Amino acids signal to mTORC1 through the Rag GTPases, which are regulated by several protein complexes, including GATOR1 and GATOR2. GATOR2, which has five components (WDR24, MIOS, WDR59, SEH1L, SEC13), is required for amino acids to activate mTORC1 and interacts with the leucine and arginine sensors Sestrin2 and CASTOR1, respectively(3–5). Despite this central role in nutrient sensing, GATOR2 remains mysterious as its subunit stoichiometry, biochemical function, and structure are unknown. Here, we used electron cryomicroscopy to determine the three-dimensional structure of the human GATOR2 complex. We find that GATOR2 adopts a large (1.1 MDa), two-fold symmetric, cage-like architecture, supported by an octagonal scaffold and decorated with eight pairs of WD40 β-propellers. The scaffold contains two WDR24, four MIOS, and two WDR59 subunits circularized via two distinct types of junctions involving non-catalytic RING domains and α-solenoids. Integration of SEH1L and SEC13 into the scaffold through β-propeller blade donation stabilizes the GATOR2 complex and reveals an evolutionary relationship to the nuclear pore and membrane coating complexes(6). The scaffold orients the WD40 β-propeller dimers, which mediate interactions with Sestrin2, CASTOR1, and GATOR1. Our work reveals the structure of an essential component of the nutrient sensing machinery and provides a foundation for understanding GATOR2 function within the mTORC1 pathway.