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- EMDB-26382: IL-27 quaternary receptor signaling complex -

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Basic information

Entry
Database: EMDB / ID: EMD-26382
TitleIL-27 quaternary receptor signaling complex
Map dataSharpened Map
Sample
  • Complex: IL-27 quaternary receptor signaling complex
    • Protein or peptide: Interleukin-27 receptor subunit alpha
    • Protein or peptide: Interleukin-6 receptor subunit beta
    • Protein or peptide: Interleukin-27 subunit beta
    • Protein or peptide: Interleukin-27 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 T-helper 17 type immune response / interleukin-27 receptor activity / negative regulation of type 2 immune response / oncostatin-M receptor complex / regulation of isotype switching to IgG isotypes / interleukin-11 receptor activity / interleukin-11 binding ...interleukin-27 receptor binding / regulation of T-helper 1 cell differentiation / negative regulation of T cell extravasation / negative regulation of T-helper 17 type immune response / interleukin-27 receptor activity / negative regulation of type 2 immune response / oncostatin-M receptor complex / regulation of isotype switching to IgG isotypes / interleukin-11 receptor activity / interleukin-11 binding / 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 / interleukin-6 receptor complex / response to Gram-positive bacterium / interleukin-11-mediated signaling pathway / positive regulation of T-helper 1 type immune response / T-helper 17 cell lineage commitment / positive regulation of adaptive immune response / positive regulation of alpha-beta T cell proliferation / positive regulation of acute inflammatory response / positive regulation of astrocyte differentiation / intestinal epithelial cell development / positive regulation of platelet aggregation / negative regulation of interleukin-17 production / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / cytokine receptor activity / T-helper 1 type immune response / glycogen metabolic process / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / regulation of T cell proliferation / cytokine binding / positive regulation of Notch signaling pathway / protein tyrosine kinase activator activity / positive regulation of cardiac muscle hypertrophy / MAPK3 (ERK1) activation / growth factor binding / MAPK1 (ERK2) activation / negative regulation of interleukin-6 production / humoral immune response / negative regulation of tumor necrosis factor production / positive regulation of vascular endothelial growth 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 / cytokine activity / response to cytokine / cytokine-mediated signaling pathway / transmembrane signaling receptor activity / positive regulation of type II interferon production / scaffold protein binding / negative regulation of neuron apoptotic process / cell surface receptor signaling pathway / receptor complex / defense response to Gram-positive bacterium / immune response / inflammatory response / membrane raft / endoplasmic reticulum lumen / external side of plasma membrane / signaling receptor binding / innate immune response / dendrite / neuronal cell body / positive regulation of cell population proliferation / negative regulation of apoptotic process / cell surface / extracellular space / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Interleukin-27 alpha / Type I cytokine receptor, cytokine-binding domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chains family signature. / 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 ...Interleukin-27 alpha / Type I cytokine receptor, cytokine-binding domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chains family signature. / 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-6 receptor subunit beta / Interleukin-27 subunit beta / Interleukin-27 receptor subunit alpha / Interleukin-27 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsCaveney NA / Glassman CR / Jude KM / Tsutsumi N / Garcia KC
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01-AI51321 United States
CitationJournal: Elife / Year: 2022
Title: Structure of the IL-27 quaternary receptor signaling complex.
Authors: Nathanael A Caveney / Caleb R Glassman / Kevin M Jude / Naotaka Tsutsumi / K Christopher Garcia /
Abstract: Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface ...Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface receptors, IL-27Rα and gp130, results in activation of receptor-associated Janus Kinases and nuclear translocation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT3 transcription factors. Despite the emerging therapeutic importance of this cytokine axis in cancer and autoimmunity, a molecular blueprint of the IL-27 receptor signaling complex, and its relation to other gp130/IL-12 family cytokines, is currently unclear. We used cryogenic-electron microscopy to determine the quaternary structure of IL-27, composed of p28 and Epstein-Barr Virus-Induced 3 (Ebi3) subunits, bound to receptors, IL-27Rα and gp130. The resulting 3.47 Å resolution structure revealed a three-site assembly mechanism nucleated by the central p28 subunit of the cytokine. The overall topology and molecular details of this binding are reminiscent of IL-6 but distinct from related heterodimeric cytokines IL-12 and IL-23. These results indicate distinct receptor assembly mechanisms used by heterodimeric cytokines with important consequences for targeted agonism and antagonism of IL-27 signaling.
History
DepositionMar 7, 2022-
Header (metadata) releaseMay 25, 2022-
Map releaseMay 25, 2022-
UpdateMay 25, 2022-
Current statusMay 25, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26382.png

Downloads & links

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Map

FileDownload / File: emd_26382.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened Map
Voxel sizeX=Y=Z: 0.839 Å
Density
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.014244547 - 2.1381838
Average (Standard dev.)0.0016247702 (±0.026853707)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 214.784 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_26382_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: IL-27 quaternary receptor signaling complex

Fileemd_26382_half_map_1.map
AnnotationIL-27 quaternary receptor signaling complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: IL-27 quaternary receptor signaling complex

Fileemd_26382_half_map_2.map
AnnotationIL-27 quaternary receptor signaling 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 quaternary receptor signaling complex

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

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Supramolecule #1: IL-27 quaternary receptor signaling complex

SupramoleculeName: IL-27 quaternary receptor signaling complex / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Interleukin-27 receptor subunit alpha

MacromoleculeName: Interleukin-27 receptor subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.053055 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AGPLQCYGVG PLGDLNCSWE PLGDLGAPSE LHLQSQKYRS NKTQTVAVAA GRSWVAIPRE QLTMSDKLLV WGTKAGQPLW PPVFVNLET QMKPNAPRLG PDVDFSEDDP LEATVHWAPP TWPSHKVLIC QFHYRRCQEA AWTLLEPELK TIPLTPVEIQ D LELATGYK ...String:
AGPLQCYGVG PLGDLNCSWE PLGDLGAPSE LHLQSQKYRS NKTQTVAVAA GRSWVAIPRE QLTMSDKLLV WGTKAGQPLW PPVFVNLET QMKPNAPRLG PDVDFSEDDP LEATVHWAPP TWPSHKVLIC QFHYRRCQEA AWTLLEPELK TIPLTPVEIQ D LELATGYK VYGRCRMEKE EDLWGEWSPI LSFQTPPS

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Macromolecule #2: Interleukin-6 receptor subunit beta

MacromoleculeName: Interleukin-6 receptor subunit beta / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.099535 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ELLDPCGYIS PESPVVQLHS NFTAVCVLKE KCMDYFHVNA NYIVWKTNHF TIPKEQYTII NRTASSVTFT DIASLNIQLT CNILTFGQL EQNVYGITII SGLPPEKPKN LSCIVNEGKK MRCEWDGGRE THLETNFTLK SEWATHKFAD CKAKRDTPTS C TVDYSTVY ...String:
ELLDPCGYIS PESPVVQLHS NFTAVCVLKE KCMDYFHVNA NYIVWKTNHF TIPKEQYTII NRTASSVTFT DIASLNIQLT CNILTFGQL EQNVYGITII SGLPPEKPKN LSCIVNEGKK MRCEWDGGRE THLETNFTLK SEWATHKFAD CKAKRDTPTS C TVDYSTVY FVNIEVWVEA ENALGKVTSD HINFDPVYKV KPNPPHNLSV INSEELSSIL KLTWTNPSIK SVIILKYNIQ YR TKDASTW SQIPPEDTAS TRSSFTVQDL KPFTEYVFRI RCMKEDGKGY WSDWSEEASG IT

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Macromolecule #3: Interleukin-27 subunit beta

MacromoleculeName: Interleukin-27 subunit beta / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.209553 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: RKGPPAALTL PRVQCRASRY PIAVDCSWTL PPAPNSTSPV SFIATYRLGM AARGHSWPCL QQTPTSTSCT ITDVQLFSMA PYVLNVTAV HPWGSSSSFV PFITEHIIKP DPPEGVRLSP LAERQLQVQW EPPGSWPFPE IFSLKYWIRY KRQGAARFHR V GPIEATSF ...String:
RKGPPAALTL PRVQCRASRY PIAVDCSWTL PPAPNSTSPV SFIATYRLGM AARGHSWPCL QQTPTSTSCT ITDVQLFSMA PYVLNVTAV HPWGSSSSFV PFITEHIIKP DPPEGVRLSP LAERQLQVQW EPPGSWPFPE IFSLKYWIRY KRQGAARFHR V GPIEATSF ILRAVRPRAR YYVQVAAQDL TDYGELSDWS LPATATMSLG

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Macromolecule #4: Interleukin-27 subunit alpha

MacromoleculeName: Interleukin-27 subunit alpha / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.56216 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: FPRPPGRPQL SLQELRREFT VSLHLARKLL SEVRGQAHRF AESHLPGVNL YLLPLGEQLP DVSLTFQAWR RLSDPERLCF ISTTLQPFH ALLGGLGTQG RWTNMERMQL WAMRLDLRDL QRHLRFQVLA AGFNLPEEEE EEEEEEEEER KGLLPGALGS A LQGPAQVS ...String:
FPRPPGRPQL SLQELRREFT VSLHLARKLL SEVRGQAHRF AESHLPGVNL YLLPLGEQLP DVSLTFQAWR RLSDPERLCF ISTTLQPFH ALLGGLGTQG RWTNMERMQL WAMRLDLRDL QRHLRFQVLA AGFNLPEEEE EEEEEEEEER KGLLPGALGS A LQGPAQVS WPQLLSTYRL LHSLELVLSR AVRELLLLSK AGHSVWPLGF PTLSPQP

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Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 4 / 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

Concentration1 mg/mL
BufferpH: 8
Component:
ConcentrationNameFormula
20.0 mMHEPES pH 8.0
150.0 mMSodium ChlorideNaClSodium chloride
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
Details: The grids were blotted for 3 seconds with an offset of 3..

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Specialist opticsEnergy filter - Name: GIF Bioquantum
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / 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: 6387370
CTF correctionSoftware - Name: cryoSPARC
Startup modelType of model: OTHER / Details: Ab initio
Initial angle assignmentType: OTHER / Software - Name: cryoSPARC
Final angle assignmentType: OTHER / Software - Name: cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 548147
FSC plot (resolution estimation)

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