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Structure of the nutrient-sensing hub GATOR2.

Valenstein ML, Rogala KB, Lalgudi PV, Brignole EJ, Gu X, Saxton RA, Chantranupong L, Kolibius J, Quast JP, Sabatini DM
Nature 607 610-616 (2022)
Cited: 14 times
EuropePMC logo PMID: 35831510

Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) controls growth by regulating anabolic and catabolic processes in response to environmental cues, including nutrients1,2. 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 and SEC13), is required for amino acids to activate mTORC1 and interacts with the leucine and arginine sensors SESN2 and CASTOR1, respectively3-5. Despite this central role in nutrient sensing, GATOR2 remains mysterious as its subunit stoichiometry, biochemical function and structure are unknown. Here we used cryo-electron microscopy to determine the three-dimensional structure of the human GATOR2 complex. We found 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 junction 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 complexes6. The scaffold orients the WD40 β-propeller dimers, which mediate interactions with SESN2, CASTOR1 and GATOR1. Our work reveals the structure of an essential component of the nutrient-sensing machinery and provides a foundation for understanding the function of GATOR2 within the mTORC1 pathway.

Articles - 7uhy mentioned but not cited (2)

  1. research-article An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway. Liu GY, Jouandin P, Bahng RE, Perrimon N, Sabatini DM. bioRxiv 2023.05.25.541239 (2023)
  2. Cryo-EM structure of the SEA complex. Tafur L, Hinterndorfer K, Gabus C, Lamanna C, Bergmann A, Sadian Y, Hamdi F, Kyrilis FL, Kastritis PL, Loewith R. Nature 611 399-404 (2022)


Reviews citing this publication (4)

  1. Longin domain GAP complexes in nutrient signalling, membrane traffic and neurodegeneration. Jansen RM, Hurley JH. FEBS Lett 597 750-761 (2023)
  2. Regulation of mTORC1 by the Rag GTPases. Lama-Sherpa TD, Jeong MH, Jewell JL. Biochem Soc Trans 51 655-664 (2023)
  3. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease. Goul C, Peruzzo R, Zoncu R. Nat Rev Mol Cell Biol 24 857-875 (2023)
  4. mTOR Signaling Pathway and Gut Microbiota in Various Disorders: Mechanisms and Potential Drugs in Pharmacotherapy. Gao Y, Tian T. Int J Mol Sci 24 11811 (2023)

Articles citing this publication (8)

  1. Mechanism of IFT-A polymerization into trains for ciliary transport. Meleppattu S, Zhou H, Dai J, Gui M, Brown A. Cell 185 4986-4998.e12 (2022)
  2. DREAMM: a web-based server for drugging protein-membrane interfaces as a novel workflow for targeted drug design. Chatzigoulas A, Cournia Z. Bioinformatics 38 5449-5451 (2022)
  3. AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation. Dai X, Jiang C, Jiang Q, Fang L, Yu H, Guo J, Yan P, Chi F, Zhang T, Inuzuka H, Asara JM, Wang P, Guo J, Wei W. Nat Metab 5 265-276 (2023)
  4. Coatomer in the universe of cellular complexity. Field MC, Rout MP. Mol Biol Cell 33 (2022)
  5. Exome sequencing identifies genes associated with sleep-related traits. Fei CJ, Li ZY, Ning J, Yang L, Wu BS, Kang JJ, Liu WS, He XY, You J, Chen SD, Yu H, Huang ZL, Feng JF, Yu JT, Cheng W. Nat Hum Behav (2024)
  6. GATOR2 rings GATOR1 to speak to mTORC1. Sahu U, Ben-Sahra I. Mol Cell 83 6-8 (2023)
  7. Selection-free endogenous tagging of cell lines by bicistronic co-expression of the surface antigen NGFR. Seibert M, Kurrle N, Stolp V, Nürnberger H, Tzschentke S, Börner L, Wempe F, Serve H, Schnütgen F. MethodsX 9 101929 (2022)
  8. Wdr59 promotes or inhibits TORC1 activity depending on cellular context. Zhang Y, Ting CY, Yang S, Reich J, Fru K, Lilly MA. Proc Natl Acad Sci U S A 120 e2212330120 (2023)


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