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- PDB-9lvj: Cryo-EM structure of Sestrin2 bound human GATOR2 complex -

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Basic information

Entry
Database: PDB / ID: 9lvj
TitleCryo-EM structure of Sestrin2 bound human GATOR2 complex
Components
  • (GATOR2 complex protein ...) x 3
  • Isoform B of Nucleoporin SEH1
  • Protein SEC13 homolog
  • Sestrin-2
KeywordsSIGNALING 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 / central nervous system myelin formation / GATOR2 complex / L-leucine binding / Atg1/ULK1 kinase complex / Seh1-associated complex / COPII-coated vesicle budding ...oligodendrocyte progenitor proliferation / regulation of response to reactive oxygen species / sulfiredoxin activity / negative regulation of translation in response to endoplasmic reticulum stress / central nervous system myelin formation / GATOR2 complex / L-leucine binding / Atg1/ULK1 kinase complex / Seh1-associated complex / COPII-coated vesicle budding / protein exit from endoplasmic reticulum / oxidoreductase activity, acting on peroxide as acceptor / regulation of TORC1 signaling / nuclear pore outer ring / positive regulation of ER to Golgi vesicle-mediated transport / nuclear pore organization / TORC2 complex / COPII-coated vesicle cargo loading / PH domain binding / cellular response to leucine starvation / activation of protein kinase activity / COPII vesicle coat / Nuclear Pore Complex (NPC) Disassembly / Regulation of Glucokinase by Glucokinase Regulatory Protein / Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) / Transport of Ribonucleoproteins into the Host Nucleus / oligodendrocyte differentiation / positive regulation of protein exit from endoplasmic reticulum / attachment of mitotic spindle microtubules to kinetochore / cellular response to L-leucine / protein-containing complex localization / Transport of the SLBP independent Mature mRNA / Transport of the SLBP Dependant Mature mRNA / Amino acids regulate mTORC1 / SUMOylation of SUMOylation proteins / nucleotide-activated protein kinase complex / Transport of Mature mRNA Derived from an Intronless Transcript / NS1 Mediated Effects on Host Pathways / TORC2 signaling / Rev-mediated nuclear export of HIV RNA / Nuclear import of Rev protein / SUMOylation of RNA binding proteins / NEP/NS2 Interacts with the Cellular Export Machinery / protein K6-linked ubiquitination / tRNA processing in the nucleus / Postmitotic nuclear pore complex (NPC) reformation / Transport of Mature mRNA derived from an Intron-Containing Transcript / COPII-mediated vesicle transport / nucleocytoplasmic transport / vacuolar membrane / cellular oxidant detoxification / GDP-dissociation inhibitor activity / Viral Messenger RNA Synthesis / SUMOylation of ubiquitinylation proteins / Vpr-mediated nuclear import of PICs / positive regulation of macroautophagy / SUMOylation of DNA replication proteins / regulation of protein phosphorylation / Oxidoreductases; Acting on a peroxide as acceptor; Peroxidases / reactive oxygen species metabolic process / Regulation of HSF1-mediated heat shock response / positive regulation of TOR signaling / mitotic metaphase chromosome alignment / mRNA transport / cellular response to glucose starvation / SUMOylation of DNA damage response and repair proteins / cellular response to nutrient levels / negative regulation of TORC1 signaling / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / positive regulation of TORC1 signaling / MHC class II antigen presentation / signaling adaptor activity / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / cellular response to amino acid stimulus / DNA damage response, signal transduction by p53 class mediator / protein localization to plasma membrane / protein import into nucleus / cellular response to amino acid starvation / Resolution of Sister Chromatid Cohesion / SUMOylation of chromatin organization proteins / HCMV Late Events / TP53 Regulates Metabolic Genes / peroxidase activity / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / ER to Golgi transport vesicle membrane / protein sequestering activity / RHO GTPases Activate Formins / negative regulation of cell growth / positive regulation of protein localization to nucleus / intracellular protein transport / regulation of autophagy / RING-type E3 ubiquitin transferase / ISG15 antiviral mechanism / autophagy / kinetochore / HCMV Early Events / Separation of Sister Chromatids / ubiquitin protein ligase activity / nuclear envelope
Similarity search - Function
Sestrin / PA26 p53-induced protein (sestrin) / WDR59, modified RING finger, H2 subclass (C3H3C2-type) / MIOS, WD40 repeat / WD repeat protein mio, zinc-ribbon like domain / GATOR complex protein WDR24 / MIOS/Sea4 / : / Zinc-ribbon like family / MIOS, alpha-solenoid ...Sestrin / PA26 p53-induced protein (sestrin) / WDR59, modified RING finger, H2 subclass (C3H3C2-type) / MIOS, WD40 repeat / WD repeat protein mio, zinc-ribbon like domain / GATOR complex protein WDR24 / MIOS/Sea4 / : / Zinc-ribbon like family / MIOS, alpha-solenoid / : / : / RING/Ubox like zinc-binding domain / AhpD-like / RWD domain profile. / RWD / RWD domain / Sec13/Seh1 family / : / Nucleolar protein 10-like, N-terminal 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 / 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: 3.82 Å
AuthorsSu, M.-Y.
Funding support China, 1items
OrganizationGrant numberCountry
Other government20231120103446003 China
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 12, 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: Protein SEC13 homolog
K: GATOR2 complex protein MIOS
L: GATOR2 complex protein MIOS
M: GATOR2 complex protein WDR24
N: GATOR2 complex protein WDR59
O: Isoform B of Nucleoporin SEH1
P: Isoform B of Nucleoporin SEH1
Q: Isoform B of Nucleoporin SEH1
R: Protein SEC13 homolog
U: Sestrin-2
V: Sestrin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,263,94850
Polymers1,261,85418
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 ABKLCMDN

#1: Protein
GATOR2 complex protein MIOS


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


Mass: 88326.953 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR24 / Production host: Homo sapiens (human) / References: UniProt: Q96S15
#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 , 3 types, 10 molecules EFGOPQHRUV

#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 Protein SEC13 homolog


Mass: 40791.668 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SEC13 / Production host: Homo sapiens (human) / References: UniProt: P55735
#6: Protein Sestrin-2


Mass: 54560.566 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SESN2 / Production host: Homo sapiens (human) / References: UniProt: P58004

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Non-polymers , 1 types, 32 molecules

#7: 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: Sestrin2 bound human GATOR2 complex / Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 0.73 mg/ml / Embedding 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: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 48.41 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
Details: The movies consist of 50 frames, with a total dose of 48.41 e-/A2, 48.41 e-/A2, or 52.41 e-/A2

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.82 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 190375 / Symmetry type: POINT
RefinementHighest resolution: 3.82 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00648685
ELECTRON MICROSCOPYf_angle_d0.73166974
ELECTRON MICROSCOPYf_dihedral_angle_d4.4667839
ELECTRON MICROSCOPYf_chiral_restr0.0468120
ELECTRON MICROSCOPYf_plane_restr0.0068903

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