9oti

GATOR2 complex bound to arginine sensor CASTOR1

Structural highlights

9oti is a 18 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 3.5Å
Ligands:	ZN
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) is a nutrient-responsive master regulator of metabolism. Amino acids control the recruitment and activation of mTORC1 at the lysosome through the nucleotide loading state of the heterodimeric Rag GTPases. Under low nutrients, including arginine, the GTPase-activating protein complex GATOR1 promotes GTP hydrolysis on RagA/B, inactivating mTORC1. GATOR1 is regulated by the cage-like GATOR2 complex and cytosolic amino acid sensors. To understand how the arginine sensor CASTOR1 binds to GATOR2 to disinhibit GATOR1 under low cytosolic arginine, we determined the cryo-electron microscopy structure of human GATOR2 bound to CASTOR1 in the absence of arginine. Two MIOS WD40 domain beta-propellers of the GATOR2 cage engage with both subunits of a single CASTOR1 homodimer. Each propeller binds to a negatively charged MIOS-binding interface on CASTOR1 that is distal to the arginine pocket. The structure shows how arginine-triggered loop ordering in CASTOR1 blocks the MIOS-binding interface, switches off its binding to GATOR2 and, thus, communicates to downstream mTORC1 activation.

Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.,Jansen RM, Maghe C, Tapia K, Wu S, Yang S, Ren X, Zoncu R, Hurley JH Nat Struct Mol Biol. 2025 Jul 25:10.1038/s41594-025-01635-0. doi: , 10.1038/s41594-025-01635-0. PMID:40715445^[8]

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

References

↑ 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:https://dx.doi.org/10.1126/science.1232044
↑ 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
↑ 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:https://dx.doi.org/10.1016/j.celrep.2014.10.019
↑ 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:https://dx.doi.org/10.1126/science.aad2087
↑ 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:https://dx.doi.org/10.1038/nature19079
↑ 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:https://dx.doi.org/10.1038/s41586-022-04939-z
↑ 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
↑ Jansen RM, Maghe C, Tapia K, Wu S, Yang S, Ren X, Zoncu R, Hurley JH. Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex. Nat Struct Mol Biol. 2025 Jul 25:10.1038/s41594-025-01635-0. PMID:40715445 doi:10.1038/s41594-025-01635-0

Proteopedia Page Contributors and Editors (what is this?)

OCA

[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:https://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:https://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:https://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:https://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:https://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] Jansen RM, Maghe C, Tapia K, Wu S, Yang S, Ren X, Zoncu R, Hurley JH. Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex. Nat Struct Mol Biol. 2025 Jul 25:10.1038/s41594-025-01635-0. PMID:40715445 doi:10.1038/s41594-025-01635-0

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9oti

GATOR2 complex bound to arginine sensor CASTOR1

Structural highlights

Function

Publication Abstract from PubMed

References

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Proteopedia Page Contributors and Editors (what is this?)

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