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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
Function / homology
Function and homology information


interleukin-27 receptor binding / regulation of T-helper 1 cell differentiation / negative regulation of T cell extravasation / negative regulation of cellular extravasation / oncostatin-M receptor activity / negative regulation of T-helper 17 type immune response / IL-6-type cytokine receptor ligand interactions / leukemia inhibitory factor receptor activity / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation ...interleukin-27 receptor binding / regulation of T-helper 1 cell differentiation / negative regulation of T cell extravasation / negative regulation of cellular extravasation / oncostatin-M receptor activity / negative regulation of T-helper 17 type immune response / IL-6-type cytokine receptor ligand interactions / leukemia inhibitory factor receptor activity / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-27 signaling / triglyceride mobilization / interleukin-6 receptor activity / interleukin-6 binding / Interleukin-6 signaling / interleukin-27 receptor activity / Interleukin-35 Signalling / negative regulation of type 2 immune response / oncostatin-M receptor complex / regulation of isotype switching to IgG isotypes / oncostatin-M-mediated signaling pathway / ciliary neurotrophic factor receptor activity / ciliary neurotrophic factor receptor binding / negative regulation of interleukin-6-mediated signaling pathway / leukemia inhibitory factor signaling pathway / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / ciliary neurotrophic factor-mediated signaling pathway / leptin-mediated signaling pathway / interleukin-6 receptor complex / response to Gram-positive bacterium / interleukin-6 receptor binding / regulation of Notch signaling pathway / positive regulation of T-helper 1 type immune response / interleukin-11-mediated signaling pathway / positive regulation of astrocyte differentiation / intestinal epithelial cell development / interleukin-12 receptor complex / interleukin-23 receptor complex / negative regulation of interleukin-17 production / cytokine receptor activity / neuronal cell body membrane / glycogen metabolic process / interleukin-6-mediated signaling pathway / regulation of T cell proliferation / positive regulation of Notch signaling pathway / protein tyrosine kinase activator activity / negative regulation of cytosolic calcium ion concentration / cytokine binding / positive regulation of activated T cell proliferation / positive regulation of smooth muscle cell migration / growth factor binding / peptide hormone binding / negative regulation of interleukin-6 production / negative regulation of tumor necrosis factor production / positive regulation of osteoblast differentiation / coreceptor activity / T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of defense response to virus by host / positive regulation of T cell proliferation / response to cytokine / cytokine activity / cytokine-mediated signaling pathway / positive regulation of type II interferon production / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / receptor complex / defense response to Gram-positive bacterium / inflammatory response / membrane raft / external side of plasma membrane / signaling receptor binding / innate immune response / neuronal cell body / dendrite / positive regulation of cell population proliferation / cell surface / signal transduction / extracellular space / extracellular region / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Interleukin-27 alpha / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Interferon/interleukin receptor domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Interferon-alpha/beta receptor, fibronectin type III ...Interleukin-27 alpha / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Interferon/interleukin receptor domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Interferon-alpha/beta receptor, fibronectin type III / 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-
UpdateOct 19, 2022-
Current statusOct 19, 2022Processing 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 / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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

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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

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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

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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 / N-Acetylglucosamine

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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 chlorideSodium 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 - 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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / 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
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
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1811398
CTF correctionSoftware - Name: cryoSPARC (ver. 3.3.1)
Details: CTF correction was performed following 3D reconstruction. Local CTF refinement was carried out during refinement
Startup modelType of model: INSILICO MODEL / In silico model: CryoSPARC ab-initio.
Initial 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.
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.1)
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

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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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