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- PDB-9lwf: Cryo-EM structure of dual sensor bound GATOR2 complex -

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Entry
Database: PDB / ID: 9lwf
TitleCryo-EM structure of dual sensor bound GATOR2 complex
Components
  • (GATOR2 complex protein ...) x 3
  • Cytosolic arginine sensor for mTORC1 subunit 1
  • Isoform 3 of Protein SEC13 homolog
  • Isoform B of Nucleoporin SEH1
  • Sestrin-2
KeywordsSTRUCTURAL PROTEIN / amino acid sensor
Function / homology
Function and homology information


oligodendrocyte progenitor proliferation / regulation of response to reactive oxygen species / sulfiredoxin activity / negative regulation of translation in response to endoplasmic reticulum stress / GATOR2 complex / L-leucine binding / cellular response to L-arginine / molecular sensor activity / Atg1/ULK1 kinase complex / Seh1-associated complex ...oligodendrocyte progenitor proliferation / regulation of response to reactive oxygen species / sulfiredoxin activity / negative regulation of translation in response to endoplasmic reticulum stress / GATOR2 complex / L-leucine binding / cellular response to L-arginine / molecular sensor activity / Atg1/ULK1 kinase complex / Seh1-associated complex / protein exit from endoplasmic reticulum / COPII-coated vesicle budding / central nervous system myelin formation / TORC2 complex / regulation of TORC1 signaling / oxidoreductase activity, acting on peroxide as acceptor / PH domain binding / cellular response to leucine starvation / nuclear pore outer ring / COPII-coated vesicle cargo loading / nuclear pore organization / COPII vesicle coat / mitochondrial DNA metabolic process / nucleotide-activated protein kinase complex / Nuclear Pore Complex (NPC) Disassembly / Regulation of Glucokinase by Glucokinase Regulatory Protein / Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) / cellular response to L-leucine / Transport of Ribonucleoproteins into the Host Nucleus / protein K6-linked ubiquitination / attachment of mitotic spindle microtubules to kinetochore / Amino acids regulate mTORC1 / Transport of the SLBP independent Mature mRNA / Transport of the SLBP Dependant Mature mRNA / NS1 Mediated Effects on Host Pathways / SUMOylation of SUMOylation proteins / protein-containing complex localization / Transport of Mature mRNA Derived from an Intronless Transcript / Rev-mediated nuclear export of HIV RNA / SUMOylation of RNA binding proteins / Nuclear import of Rev protein / NEP/NS2 Interacts with the Cellular Export Machinery / Transport of Mature mRNA derived from an Intron-Containing Transcript / tRNA processing in the nucleus / COPII-mediated vesicle transport / Postmitotic nuclear pore complex (NPC) reformation / arginine binding / positive regulation of lipophagy / vacuolar membrane / nucleocytoplasmic transport / triglyceride homeostasis / GDP-dissociation inhibitor activity / regulation of gluconeogenesis / Viral Messenger RNA Synthesis / cellular oxidant detoxification / mitotic metaphase chromosome alignment / fatty acid beta-oxidation / SUMOylation of ubiquitinylation proteins / Vpr-mediated nuclear import of PICs / regulation of cAMP/PKA signal transduction / : / regulation of protein phosphorylation / oligodendrocyte differentiation / SUMOylation of DNA replication proteins / positive regulation of macroautophagy / Oxidoreductases; Acting on a peroxide as acceptor; Peroxidases / Regulation of HSF1-mediated heat shock response / positive regulation of TOR signaling / mRNA transport / response to glucose / nuclear pore / cellular response to nutrient levels / SUMOylation of DNA damage response and repair proteins / cellular response to glucose starvation / negative regulation of TORC1 signaling / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / positive regulation of TORC1 signaling / signaling adaptor activity / MHC class II antigen presentation / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / protein sequestering activity / reactive oxygen species metabolic process / cellular response to amino acid starvation / SUMOylation of chromatin organization proteins / Resolution of Sister Chromatid Cohesion / HCMV Late Events / TP53 Regulates Metabolic Genes / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / cellular response to amino acid stimulus / intracellular protein transport / DNA damage response, signal transduction by p53 class mediator / peroxidase activity / ER to Golgi transport vesicle membrane / Transcriptional regulation by small RNAs / RHO GTPases Activate Formins / negative regulation of cell growth / response to insulin / RING-type E3 ubiquitin transferase / kinetochore
Similarity search - Function
Sestrin / PA26 p53-induced protein (sestrin) / WDR59, modified RING finger, H2 subclass (C3H3C2-type) / MIOS, WD40 repeat / CASTOR family / CASTOR1, N-terminal / : / Cytosolic arginine sensor for mTORC1 subunit 1 N-terminal domain / Cytosolic arginine sensor for mTORC1 subunit 1/2, ACT-like / : ...Sestrin / PA26 p53-induced protein (sestrin) / WDR59, modified RING finger, H2 subclass (C3H3C2-type) / MIOS, WD40 repeat / CASTOR family / CASTOR1, N-terminal / : / Cytosolic arginine sensor for mTORC1 subunit 1 N-terminal domain / Cytosolic arginine sensor for mTORC1 subunit 1/2, ACT-like / : / WD repeat protein mio, zinc-ribbon like domain / GATOR complex protein WDR24 / MIOS/Sea4 / : / Zinc-ribbon like family / MIOS, alpha-solenoid / CASTOR, ACT domain / : / : / RING/Ubox like zinc-binding domain / ACT domain / AhpD-like / RWD domain profile. / RWD / RWD domain / Sec13/Seh1 family / ACT-like domain / Ubiquitin-conjugating enzyme/RWD-like / WD domain, G-beta repeat / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Protein SEC13 homolog / Sestrin-2 / GATOR2 complex protein WDR59 / Cytosolic arginine sensor for mTORC1 subunit 1 / Nucleoporin SEH1 / GATOR2 complex protein WDR24 / GATOR2 complex protein MIOS
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsSu, M.-Y.
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: Cell Rep / Year: 2025
Title: Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex.
Authors: Ming-Yuan Su / Fei Teng / Shan Wang / Xinyi Mai / Huan Zeng / Juan Li / Xiaoxiao Song / Xi Wang / Goran Stjepanovic /
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, ...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.
History
DepositionFeb 14, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 13, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GATOR2 complex protein MIOS
B: GATOR2 complex protein MIOS
C: GATOR2 complex protein WDR24
D: GATOR2 complex protein WDR59
E: Isoform B of Nucleoporin SEH1
F: Isoform B of Nucleoporin SEH1
G: Isoform B of Nucleoporin SEH1
H: Isoform 3 of Protein SEC13 homolog
I: GATOR2 complex protein WDR24
K: GATOR2 complex protein MIOS
L: GATOR2 complex protein MIOS
N: GATOR2 complex protein WDR59
O: Isoform B of Nucleoporin SEH1
P: Isoform B of Nucleoporin SEH1
Q: Isoform B of Nucleoporin SEH1
R: Isoform 3 of Protein SEC13 homolog
U: Cytosolic arginine sensor for mTORC1 subunit 1
V: Cytosolic arginine sensor for mTORC1 subunit 1
X: Sestrin-2
Y: Sestrin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,336,44652
Polymers1,334,35320
Non-polymers2,09332
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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GATOR2 complex protein ... , 3 types, 8 molecules ABKLCIDN

#1: Protein
GATOR2 complex protein MIOS / Missing oocyte meiosis regulator homolog


Mass: 98700.391 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MIOS / Production host: Homo sapiens (human) / References: UniProt: Q9NXC5
#2: Protein GATOR2 complex protein WDR24 / WD repeat-containing protein 24


Mass: 88326.953 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR24, C16orf21, JFP7 / Production host: Homo sapiens (human)
References: UniProt: Q96S15, RING-type E3 ubiquitin transferase
#3: Protein GATOR2 complex protein WDR59 / WD repeat-containing protein 59


Mass: 109938.391 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR59, KIAA1923, FP977 / Production host: Homo sapiens (human) / References: UniProt: Q6PJI9

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Protein , 4 types, 12 molecules EFGOPQHRUVXY

#4: Protein
Isoform B of Nucleoporin SEH1 / GATOR2 complex protein SEH1 / Nup107-160 subcomplex subunit SEH1 / SEC13-like protein


Mass: 46636.289 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SEH1L, SEC13L, SEH1 / Production host: Homo sapiens (human) / References: UniProt: Q96EE3
#5: Protein Isoform 3 of Protein SEC13 homolog / GATOR2 complex protein SEC13 / SEC13-like protein 1 / SEC13-related protein


Mass: 40791.668 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SEC13, D3S1231E, SEC13A, SEC13L1, SEC13R / Production host: Homo sapiens (human) / References: UniProt: P55735
#6: Protein Cytosolic arginine sensor for mTORC1 subunit 1 / Cellular arginine sensor for mTORC1 protein 1 / GATS-like protein 3


Mass: 36265.234 Da / Num. of mol.: 2 / Mutation: D304A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASTOR1, GATSL3 / Production host: Homo sapiens (human) / References: UniProt: Q8WTX7
#7: Protein Sestrin-2 / Hypoxia-induced gene


Mass: 54544.566 Da / Num. of mol.: 2 / Mutation: Y375F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SESN2, Hi95, SEST2 / Production host: Homo sapiens (human)
References: UniProt: P58004, Oxidoreductases; Acting on a peroxide as acceptor; Peroxidases

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Non-polymers , 1 types, 32 molecules

#8: Chemical...
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 32 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: dual sensor bound GATOR2 complex / Type: COMPLEX / Entity ID: #1-#7 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 48.87 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
Details: The total dose on the specimen was 48.87, 48.86 and 49.03 e-/A2 fractionated over 50 frames.

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 586448 / Symmetry type: POINT
RefinementHighest resolution: 3.41 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00658643
ELECTRON MICROSCOPYf_angle_d0.74980363
ELECTRON MICROSCOPYf_dihedral_angle_d4.9538558
ELECTRON MICROSCOPYf_chiral_restr0.0469481
ELECTRON MICROSCOPYf_plane_restr0.00510220

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