7uhy

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Human GATOR2 complexHuman GATOR2 complex

Structural highlights

7uhy is a 10 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.66Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MIOS_HUMAN As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:23723238, PubMed:26586190, PubMed:27487210, PubMed:35831510, PubMed:36528027). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:26586190, PubMed:27487210, PubMed:35831510, PubMed:36528027). GATOR2 probably acts as an E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:25263562, PubMed:25457612, PubMed:26586190, PubMed:27487210). Within the GATOR2 complex, MIOS is required to prevent autoubiquitination of WDR24, the catalytic subunit of the complex (PubMed:35831510). The GATOR2 complex is required for brain myelination (By similarity).[UniProtKB:Q8VE19][1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

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 and SEC13), is required for amino acids to activate mTORC1 and interacts with the leucine and arginine sensors SESN2 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 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 beta-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 alpha-solenoids. Integration of SEH1L and SEC13 into the scaffold through beta-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 beta-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.

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. 2022 Jul;607(7919):610-616. doi: 10.1038/s41586-022-04939-z. Epub 2022 , Jul 13. PMID:35831510[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013 May 31;340(6136):1100-6. doi: 10.1126/science.1232044. PMID:23723238 doi:http://dx.doi.org/10.1126/science.1232044
  2. ↑ Chantranupong L, Wolfson RL, Orozco JM, Saxton RA, Scaria SM, Bar-Peled L, Spooner E, Isasa M, Gygi SP, Sabatini DM. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 2014 Oct 9;9(1):1-8. PMID:25263562 doi:10.1016/j.celrep.2014.09.014
  3. ↑ Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim YC, Akopiants K, Guan KL, Karin M, Budanov AV. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 2014 Nov 20;9(4):1281-91. doi: 10.1016/j.celrep.2014.10.019. PMID:25457612 doi:http://dx.doi.org/10.1016/j.celrep.2014.10.019
  4. ↑ Saxton RA, Knockenhauer KE, Wolfson RL, Chantranupong L, Pacold ME, Wang T, Schwartz TU, Sabatini DM. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2015 Nov 19. pii: aad2087. PMID:26586190 doi:http://dx.doi.org/10.1126/science.aad2087
  5. ↑ Saxton RA, Chantranupong L, Knockenhauer KE, Schwartz TU, Sabatini DM. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature. 2016 Aug 11;536(7615):229-33. PMID:27487210 doi:http://dx.doi.org/10.1038/nature19079
  6. ↑ Valenstein ML, Rogala KB, Lalgudi PV, Brignole EJ, Gu X, Saxton RA, Chantranupong L, Kolibius J, Quast JP, Sabatini DM. Structure of the nutrient-sensing hub GATOR2. Nature. 2022 Jul;607(7919):610-616. doi: 10.1038/s41586-022-04939-z. Epub 2022, Jul 13. PMID:35831510 doi:http://dx.doi.org/10.1038/s41586-022-04939-z
  7. ↑ Jiang C, Dai X, He S, Zhou H, Fang L, Guo J, Liu S, Zhang T, Pan W, Yu H, Fu T, Li D, Inuzuka H, Wang P, Xiao J, Wei W. Ring domains are essential for GATOR2-dependent mTORC1 activation. Mol Cell. 2023 Jan 5;83(1):74-89.e9. PMID:36528027 doi:10.1016/j.molcel.2022.11.021
  8. ↑ Valenstein ML, Rogala KB, Lalgudi PV, Brignole EJ, Gu X, Saxton RA, Chantranupong L, Kolibius J, Quast JP, Sabatini DM. Structure of the nutrient-sensing hub GATOR2. Nature. 2022 Jul;607(7919):610-616. doi: 10.1038/s41586-022-04939-z. Epub 2022, Jul 13. PMID:35831510 doi:http://dx.doi.org/10.1038/s41586-022-04939-z

7uhy, resolution 3.66Å

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