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- PDB-9i3u: Cryo-EM structure of the AGR2 dimer in complex with the monomeric... -

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Basic information

Entry
Database: PDB / ID: 9i3u
TitleCryo-EM structure of the AGR2 dimer in complex with the monomeric IRE1beta luminal domain
Components
  • Anterior gradient protein 2 homolog
  • Serine/threonine-protein kinase/endoribonuclease IRE2
KeywordsCHAPERONE / endoplasmic reticulum (ER) / molecular chaperones/ protein multimerisation/ unfolded protein response (UPR)
Function / homology
Function and homology information


lung goblet cell differentiation / positive regulation of PERK-mediated unfolded protein response / apoptotic chromosome condensation / IRE1-TRAF2-ASK1 complex / endoplasmic reticulum quality control compartment / mucus secretion / dystroglycan binding / rRNA catabolic process / positive regulation of developmental growth / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters ...lung goblet cell differentiation / positive regulation of PERK-mediated unfolded protein response / apoptotic chromosome condensation / IRE1-TRAF2-ASK1 complex / endoplasmic reticulum quality control compartment / mucus secretion / dystroglycan binding / rRNA catabolic process / positive regulation of developmental growth / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters / positive regulation of cell-substrate adhesion / epidermal growth factor receptor binding / positive regulation of epidermal growth factor receptor signaling pathway / IRE1-mediated unfolded protein response / digestive tract morphogenesis / positive regulation of IRE1-mediated unfolded protein response / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / RNA endonuclease activity / response to endoplasmic reticulum stress / positive regulation of protein localization to plasma membrane / mRNA processing / unfolded protein binding / endonuclease activity / protein phosphorylation / non-specific serine/threonine protein kinase / inflammatory response / protein serine kinase activity / negative regulation of DNA-templated transcription / protein serine/threonine kinase activity / positive regulation of gene expression / magnesium ion binding / endoplasmic reticulum / extracellular space / extracellular region / ATP binding / identical protein binding / cytosol
Similarity search - Function
: / Thioredoxin-like / Serine/threonine-protein kinase/endoribonuclease IRE1/2-like / KEN domain / KEN domain superfamily / Ribonuclease 2-5A / KEN domain profile. / domain in protein kinases, N-glycanases and other nuclear proteins / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat ...: / Thioredoxin-like / Serine/threonine-protein kinase/endoribonuclease IRE1/2-like / KEN domain / KEN domain superfamily / Ribonuclease 2-5A / KEN domain profile. / domain in protein kinases, N-glycanases and other nuclear proteins / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat / Quinoprotein alcohol dehydrogenase-like superfamily / Thioredoxin-like superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Anterior gradient protein 2 homolog / Serine/threonine-protein kinase/endoribonuclease IRE2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsYan, Y. / Hardwick, S. / Tung, J. / Ron, D.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome TrustSGAG/182 United Kingdom
CitationJournal: Mol Cell / Year: 2025
Title: A structural basis for chaperone repression of stress signaling from the endoplasmic reticulum.
Authors: Lisa Neidhardt / Joanne Tung / Miriam Kuchersky / Jakub Milczarek / Vasileios Kargas / Katherine Stott / Rina Rosenzweig / David Ron / Yahui Yan /
Abstract: The endoplasmic reticulum (ER) unfolded protein response (UPR) is tuned by the balance between unfolded proteins and chaperones. Reserve chaperones suppress UPR transducers via their stress-sensing ...The endoplasmic reticulum (ER) unfolded protein response (UPR) is tuned by the balance between unfolded proteins and chaperones. Reserve chaperones suppress UPR transducers via their stress-sensing luminal domains, but the underlying mechanisms remain unclear. The ER chaperone AGR2 is known to repress the UPR transducer IRE1β. Here, structural prediction, X-ray crystallography, and NMR spectroscopy identify critical interactions between an AGR2 monomer and a regulatory loop in IRE1β's luminal domain. However, in the repressive complex, it is an AGR2 dimer that binds IRE1β. Cryoelectron microscopy (cryo-EM) reconstruction explains this feature: one AGR2 protomer engages the regulatory loop, while the second asymmetrically binds IRE1β's luminal domain's C terminus, blocking IRE1β-activating dimerization. Molecular dynamic simulations indicate that the second, disruptive AGR2 protomer exploits rare fluctuations in the IRE1β dimer that expose its binding site. Thus, AGR2 disrupts IRE1β dimers to suppress the UPR, priming the system for activation by chaperone clients that compete for AGR2.
History
DepositionJan 24, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 22, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 22, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 29, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.pdbx_database_id_DOI / _citation.year / _em_admin.last_update
Revision 1.2Nov 5, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.3Nov 19, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Anterior gradient protein 2 homolog
D: Anterior gradient protein 2 homolog
A: Serine/threonine-protein kinase/endoribonuclease IRE2


Theoretical massNumber of molelcules
Total (without water)79,0843
Polymers79,0843
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Both gel filtration and mass spectrometry confirm a 2:1 stoichiometry for the complex.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Anterior gradient protein 2 homolog / AG-2 / hAG-2 / HPC8 / Secreted cement gland protein XAG-2 homolog


Mass: 17845.541 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AGR2, AG2, UNQ515/PRO1030 / Production host: Escherichia coli (E. coli) / References: UniProt: O95994
#2: Protein Serine/threonine-protein kinase/endoribonuclease IRE2 / Endoplasmic reticulum-to-nucleus signaling 2 / Inositol-requiring protein 2 / hIRE2p / Ire1-beta / ...Endoplasmic reticulum-to-nucleus signaling 2 / Inositol-requiring protein 2 / hIRE2p / Ire1-beta / IRE1b / IRE1beta luminal domain


Mass: 43393.164 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERN2, IRE2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q76MJ5, non-specific serine/threonine protein kinase, Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters
Has protein modificationN

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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: The complex of AGR2 and IRE1beta luminal domain / Type: COMPLEX / Details: Co-expressed in E.coli. / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia (bacteria)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
2200 mMtris(hydroxymethyl)aminomethaneTris1
30.2 mMtris(2-carboxyethyl)phosphineTCEP1
SpecimenConc.: 3.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: The complex elutes as a peak cooresponding to a complex containing two copies of AGR2 and one copy of IRE1beta luminal domain.
Specimen supportGrid type: UltrAuFoil R0./1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 281.15 K

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 11.95 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategoryDetails
7UCSF ChimeraX1.9model fittinglocal EM fitting
9cryoSPARC4.6.0initial Euler assignment
10cryoSPARC4.6.0final Euler assignment
11cryoSPARC4.6.0classification
12cryoSPARC4.6.03D reconstruction
19PHENIX1.21.2_5419model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 313426 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model building

3D fitting-ID: 1

IDPDB-IDPdb chain-IDAccession codeChain residue rangeInitial refinement model-IDSource nameTypeChain-ID
1AF-Q76MJ5-F135-4291AlphaFoldin silico model
29I3F

9i3f

A9I3FPDBexperimental modelA
39I3F

9i3f

C9I3FPDBexperimental modelC
RefinementHighest resolution: 2.9 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034554
ELECTRON MICROSCOPYf_angle_d0.576198
ELECTRON MICROSCOPYf_dihedral_angle_d4.894609
ELECTRON MICROSCOPYf_chiral_restr0.04712
ELECTRON MICROSCOPYf_plane_restr0.006776

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