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- EMDB-14427: IL-27 signalling complex -

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Basic information

Entry
Database: EMDB / ID: EMD-14427
TitleIL-27 signalling complex
Map dataCryoEM map of the IL-27 signalling complex.
Sample
  • Complex: IL-27 Signalling complex
    • Protein or peptide: Interleukin-6 receptor subunit beta
    • Protein or peptide: Interleukin-27 subunit beta,Interleukin-27 subunit alpha
    • Protein or peptide: Interleukin-27 receptor subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsCytokine / immunosuppression / EBI3 / IL-27R-alpha / gp130 / p28.
Function / homology
Function and homology information


negative regulation of T cell extravasation / interleukin-27 receptor binding / regulation of T-helper 1 cell differentiation / negative regulation of cellular extravasation / negative regulation of T-helper 17 type immune response / oncostatin-M receptor activity / IL-6-type cytokine receptor ligand interactions / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-27 signaling ...negative regulation of T cell extravasation / interleukin-27 receptor binding / regulation of T-helper 1 cell differentiation / negative regulation of cellular extravasation / negative regulation of T-helper 17 type immune response / oncostatin-M receptor activity / IL-6-type cytokine receptor ligand interactions / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-27 signaling / leukemia inhibitory factor receptor activity / interleukin-6 receptor activity / interleukin-6 binding / Interleukin-6 signaling / interleukin-27 receptor activity / Interleukin-35 Signalling / regulation of isotype switching to IgG isotypes / negative regulation of type 2 immune response / oncostatin-M receptor complex / ciliary neurotrophic factor receptor binding / ciliary neurotrophic factor receptor complex / interleukin-6 receptor complex / response to Gram-positive bacterium / interleukin-27-mediated signaling pathway / interleukin-6 receptor binding / interleukin-11-mediated signaling pathway / positive regulation of T-helper 1 type immune response / regulation of Notch signaling pathway / positive regulation of astrocyte differentiation / intestinal epithelial cell development / negative regulation of interleukin-17 production / cell surface receptor signaling pathway via STAT / cytokine receptor activity / glycogen metabolic process / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / negative regulation of interleukin-6 production / regulation of T cell proliferation / protein tyrosine kinase activator activity / negative regulation of tumor necrosis factor production / positive regulation of osteoblast differentiation / positive regulation of T cell proliferation / T cell proliferation / coreceptor activity / positive regulation of defense response to virus by host / cytokine activity / cytokine-mediated signaling pathway / positive regulation of type II interferon production / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / defense response to Gram-positive bacterium / inflammatory response / membrane raft / external side of plasma membrane / signaling receptor binding / innate immune response / neuronal cell body / positive regulation of cell population proliferation / dendrite / cell surface / signal transduction / extracellular space / extracellular region / identical protein binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Interleukin-27 alpha / IL27B N-terminal FN3 domain / : / : / : / Type I cytokine receptor, cytokine-binding domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding ...Interleukin-27 alpha / IL27B N-terminal FN3 domain / : / : / : / Type I cytokine receptor, cytokine-binding domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Four-helical cytokine-like, core / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-27 subunit beta / Interleukin-27 receptor subunit alpha / Interleukin-6 receptor subunit beta / Interleukin-27 subunit alpha
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsJin Y / Gardner S / Bubeck D
Funding support United Kingdom, European Union, 2 items
OrganizationGrant numberCountry
Wellcome Trust202323/Z/16/Z United Kingdom
European Research Council (ERC)206-STGEuropean Union
CitationJournal: EMBO Rep / Year: 2022
Title: Structural insights into the assembly and activation of the IL-27 signaling complex.
Authors: Yibo Jin / Paul K Fyfe / Scott Gardner / Stephan Wilmes / Doryen Bubeck / Ignacio Moraga /
Abstract: Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the ...Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.
History
DepositionFeb 23, 2022-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14427.png

Downloads & links

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Map

FileDownload / File: emd_14427.map.gz / Format: CCP4 / Size: 35.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM map of the IL-27 signalling complex.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 210 pix.
= 222.6 Å		1.06 Å/pix.
x 210 pix.
= 222.6 Å		1.06 Å/pix.
x 210 pix.
= 222.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.7405622 - 1.120074
Average (Standard dev.)0.0009186794 (±0.019274749)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions210210210
Spacing210210210
CellA=B=C: 222.59999 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: CryoEM half map of the IL-27 signalling complex.

Fileemd_14427_half_map_1.map
AnnotationCryoEM half map of the IL-27 signalling complex.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: CryoEM half map of the IL-27 signalling complex.

Fileemd_14427_half_map_2.map
AnnotationCryoEM half map of the IL-27 signalling complex.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : IL-27 Signalling complex

EntireName: IL-27 Signalling complex
Components
  • Complex: IL-27 Signalling complex
    • Protein or peptide: Interleukin-6 receptor subunit beta
    • Protein or peptide: Interleukin-27 subunit beta,Interleukin-27 subunit alpha
    • Protein or peptide: Interleukin-27 receptor subunit alpha
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: IL-27 Signalling complex

SupramoleculeName: IL-27 Signalling complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 100 KDa

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Macromolecule #1: Interleukin-6 receptor subunit beta

MacromoleculeName: Interleukin-6 receptor subunit beta / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 32.91402 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: CGYIYPEFPV VQRGSNFTAI CVLKEACLQH YYVNASYIVW KTNHAAVPRE QVTVINRTTS SVTFTDVVLP SVQLTCNILS FGQIEQNVY GVTMLSGFPP DKPTNLTCIV NEGKNMLCQW DPGRETYLET NYTLKSEWAT EKFPDCQSKH GTSCMVSYMP T YYVNIEVW ...String:
CGYIYPEFPV VQRGSNFTAI CVLKEACLQH YYVNASYIVW KTNHAAVPRE QVTVINRTTS SVTFTDVVLP SVQLTCNILS FGQIEQNVY GVTMLSGFPP DKPTNLTCIV NEGKNMLCQW DPGRETYLET NYTLKSEWAT EKFPDCQSKH GTSCMVSYMP T YYVNIEVW VEAENALGKV SSESINFDPV DKVKPTPPYN LSVTNSEELS SILKLSWVSS GLGGLLDLKS DIQYRTKDAS TW IQVPLED TMSPRTSFTV QDLKPFTEYV FRIRSIKDSG KGYWSDWSEE ASGTT

UniProtKB: Interleukin-6 receptor subunit beta

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Macromolecule #2: Interleukin-27 subunit beta,Interleukin-27 subunit alpha

MacromoleculeName: Interleukin-27 subunit beta,Interleukin-27 subunit alpha
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 52.475281 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MVSAIVLYVL LAAAAHSAFA GSYTETALVA LSQPRVQCHA SRYPVAVDCS WTPLQAPNST RSTSFIATYR LGVATQQQSQ PCLQRSPQA SRCTIPDVHL FSTVPYMLNV TAVHPGGASS SLLAFVAERI IKPDPPEGVR LRTAGQRLQV LWHPPASWPF P DIFSLKYR ...String:
MVSAIVLYVL LAAAAHSAFA GSYTETALVA LSQPRVQCHA SRYPVAVDCS WTPLQAPNST RSTSFIATYR LGVATQQQSQ PCLQRSPQA SRCTIPDVHL FSTVPYMLNV TAVHPGGASS SLLAFVAERI IKPDPPEGVR LRTAGQRLQV LWHPPASWPF P DIFSLKYR LRYRRRGASH FRQVGPIEAT TFTLRNSKPH AKYCIQVSAQ DLTDYGKPSD WSLPGQVESA PHKPRGGGGS GG GGSVESG ENLYFQGFPT DPLSLQELRR EFTVSLYLAR KLLSEVQGYV HSFAESRLPG VNLDLLPLGY HLPNVSLTFQ AWH HLSDSE RLCFLATTLR PFPAMLGGLG TQGTWTSSER EQLWAMRLDL RDLHRHLRFQ VLAAGFKCSK EEEDKEEEEE EEEE EKKLP LGALGGPNQV SSQVSWPQLL YTYQLLHSLE LVLSRAVRDL LLLSLPRRPG SAWDSAAAHH HHHHHH

UniProtKB: Interleukin-27 subunit beta, Interleukin-27 subunit alpha

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Macromolecule #3: Interleukin-27 receptor subunit alpha

MacromoleculeName: Interleukin-27 receptor subunit alpha / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 25.968398 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MVSAIVLYVL LAAAAHSAFA GSHGSPGPLQ CYSVGPLGIL NCSWEPLGDL ETPPVLYHQS QKYHPNRVWE VKVPSKQSWV TIPREQFTM ADKLLIWGTQ KGRPLWSSVS VNLETQMKPD TPQIFSQVDI SEEATLEATV QWAPPVWPPQ KVLICQFRYK E CQAETWTR ...String:
MVSAIVLYVL LAAAAHSAFA GSHGSPGPLQ CYSVGPLGIL NCSWEPLGDL ETPPVLYHQS QKYHPNRVWE VKVPSKQSWV TIPREQFTM ADKLLIWGTQ KGRPLWSSVS VNLETQMKPD TPQIFSQVDI SEEATLEATV QWAPPVWPPQ KVLICQFRYK E CQAETWTR LEPQLKTDGL TPVEMQNLEP GTCYQVSGRC QVENGYPWGE WSSPLSFQTP FAAAHHHHHH HH

UniProtKB: Interleukin-27 receptor subunit alpha

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.1 mg/mL
BufferpH: 7.2
Component:
ConcentrationFormulaName
20.0 mMHEPESHEPES
150.0 mMNaClSodium chloride

Details: Solutions were made fresh and 0.2um filtered
GridModel: EMS Lacey Carbon / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV / Details: Blot time 2s, blot force -2.
Details0.8mg/ml

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 4092 pixel / Digitization - Dimensions - Height: 5760 pixel / Number grids imaged: 2 / Number real images: 56523 / Average exposure time: 3.5 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1811398
Startup modelType of model: INSILICO MODEL / In silico model: CryoSPARC ab-initio.
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.1)
Details: Final reconstruction was performed using local refinement in cryoSPARC.
Number images used: 208431
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.1)
Final 3D classificationNumber classes: 5 / Avg.num./class: 400000 / Software - Name: cryoSPARC (ver. 3.3.1)
Details: Final 3D classification was performed using heterogeneous refinement in cryoSPARC.

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Atomic model buiding 1

DetailsInitial fitting was performed using Chimera and ChimeraX. Then ISOLDE and Phenix real space refine were used to refine the model.
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7z0l:
IL-27 signalling complex

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