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- EMDB-26837: Structure of the IL-17A-IL-17RA-IL-17RC ternary complex -

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Basic information

Entry
Database: EMDB / ID: EMD-26837
TitleStructure of the IL-17A-IL-17RA-IL-17RC ternary complex
Map datasharpened map
Sample
  • Complex: IL-17A-IL-17RA-IL-17RC ternary complex
    • Protein or peptide: Interleukin-17A
    • Protein or peptide: Interleukin-17 receptor A
    • Protein or peptide: Isoform 5 of Interleukin-17 receptor C
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


interleukin-17 receptor activity / positive regulation of interleukin-16 production / granulocyte migration / granulocyte chemotaxis / positive regulation of antimicrobial peptide production / Interleukin-17 signaling / T-helper 17 type immune response / intestinal epithelial structure maintenance / negative regulation of inflammatory response to wounding / interleukin-17A-mediated signaling pathway ...interleukin-17 receptor activity / positive regulation of interleukin-16 production / granulocyte migration / granulocyte chemotaxis / positive regulation of antimicrobial peptide production / Interleukin-17 signaling / T-helper 17 type immune response / intestinal epithelial structure maintenance / negative regulation of inflammatory response to wounding / interleukin-17A-mediated signaling pathway / positive regulation of interleukin-23 production / positive regulation of chemokine (C-X-C motif) ligand 1 production / cell death / interleukin-17-mediated signaling pathway / positive regulation of bicellular tight junction assembly / positive regulation of interleukin-5 production / fibroblast activation / positive regulation of cytokine production involved in inflammatory response / positive regulation of osteoclast differentiation / positive regulation of interleukin-13 production / keratinocyte proliferation / defense response to fungus / cellular response to interleukin-1 / coreceptor activity / keratinocyte differentiation / Notch signaling pathway / positive regulation of interleukin-12 production / positive regulation of interleukin-1 beta production / cytokine activity / protein catabolic process / response to virus / response to wounding / positive regulation of inflammatory response / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / cell-cell signaling / gene expression / Interleukin-4 and Interleukin-13 signaling / defense response to Gram-negative bacterium / adaptive immune response / cell surface receptor signaling pathway / defense response to Gram-positive bacterium / immune response / inflammatory response / protein heterodimerization activity / external side of plasma membrane / signaling receptor binding / innate immune response / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / cell surface / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Interleukin-17 receptor C/E, N-terminal / Interleukin-17 receptor extracellular region / Interleukin 17 receptor D / Interleukin-17 receptor, fibronectin-III-like domain 1 / Interleukin-17 receptor A/B, FnIII-like domain 1 superfamily / Interleukin-17 receptor A/B, FnIII-like domain 2 superfamily / Interleukin-17 receptor, fibronectin-III-like domain 1 / Interleukin-17 receptor-like / SEFIR domain / SEFIR domain ...Interleukin-17 receptor C/E, N-terminal / Interleukin-17 receptor extracellular region / Interleukin 17 receptor D / Interleukin-17 receptor, fibronectin-III-like domain 1 / Interleukin-17 receptor A/B, FnIII-like domain 1 superfamily / Interleukin-17 receptor A/B, FnIII-like domain 2 superfamily / Interleukin-17 receptor, fibronectin-III-like domain 1 / Interleukin-17 receptor-like / SEFIR domain / SEFIR domain / SEFIR domain profile. / Interleukin-17, chordata / Interleukin-17 family / Interleukin-17 / Cystine-knot cytokine
Similarity search - Domain/homology
Interleukin-17A / Interleukin-17 receptor C / Interleukin-17 receptor A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsWilson SC / Caveney NA / Jude KM / 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: Nature / Year: 2022
Title: Organizing structural principles of the IL-17 ligand-receptor axis.
Authors: Steven C Wilson / Nathanael A Caveney / Michelle Yen / Christoph Pollmann / Xinyu Xiang / Kevin M Jude / Maximillian Hafer / Naotaka Tsutsumi / Jacob Piehler / K Christopher Garcia /
Abstract: The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases. The compositions and structures of functional IL-17 family ...The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases. The compositions and structures of functional IL-17 family ligand-receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses. Here we studied IL-25-IL-17RB binary and IL-25-IL-17RB-IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25-IL-17RB-IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25-IL-17RB homodimer is flanked by two 'wing-like' IL-17RA co-receptors through a 'tip-to-tip' geometry that is the key receptor-receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB-IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A-IL-17RA and IL-17A-IL-17RA-IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor.
History
DepositionMay 3, 2022-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateSep 28, 2022-
Current statusSep 28, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26837.png

Downloads & links

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Map

FileDownload / File: emd_26837.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 1.066 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.022608638 - 1.9965458
Average (Standard dev.)0.00093908655 (±0.019681375)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 272.896 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_26837_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_26837_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_26837_half_map_2.map
Annotationhalf map B
Projections & Slices
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Sample components

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Entire : IL-17A-IL-17RA-IL-17RC ternary complex

EntireName: IL-17A-IL-17RA-IL-17RC ternary complex
Components
  • Complex: IL-17A-IL-17RA-IL-17RC ternary complex
    • Protein or peptide: Interleukin-17A
    • Protein or peptide: Interleukin-17 receptor A
    • Protein or peptide: Isoform 5 of Interleukin-17 receptor C
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: IL-17A-IL-17RA-IL-17RC ternary complex

SupramoleculeName: IL-17A-IL-17RA-IL-17RC ternary complex / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Interleukin-17A

MacromoleculeName: Interleukin-17A / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.311678 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GITIPRNPGC PNSEDKNFPR TVMVNLNIHN RNTNTNPKRS SDYYNRSTSP WNLHRNEDPE RYPSVIWEAK CRHLGCINAD GNVDYHMNS VPIQQEILVL RREPPHCPNS FRLEKILVSV GCTCVTPIVH HVAGAPGSAL EVLFQGPGAA GLNDIFEAQK I EWHEHHHH HH

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Macromolecule #2: Interleukin-17 receptor A

MacromoleculeName: Interleukin-17 receptor A / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.888617 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LRLLDHRALV CSQPGLNCTV KNSTCLDDSW IHPRNLTPSS PKDLQIQLHF AHTQQGDLFP VAHIEWTLQT DASILYLEGA ELSVLQLNT NERLCVRFEF LSKLRHHHRR WRFTFSHFVV DPDQEYEVTV HHLPKPIPDG DPNHQSKNFL VPDCEHARMK V TTPCMSSG ...String:
LRLLDHRALV CSQPGLNCTV KNSTCLDDSW IHPRNLTPSS PKDLQIQLHF AHTQQGDLFP VAHIEWTLQT DASILYLEGA ELSVLQLNT NERLCVRFEF LSKLRHHHRR WRFTFSHFVV DPDQEYEVTV HHLPKPIPDG DPNHQSKNFL VPDCEHARMK V TTPCMSSG SLWDPNITVE TLEAHQLRVS FTLWNESTHY QILLTSFPHM ENHSCFEHMH HIPAPRPEEF HQRSNVTLTL RN LKGCCRH QVQIQPFFSS CLNDCLRHSA TVSCPEMPDT PEPIPDYMSA ALEVLFQGPG AAEDQVDPRL IDGKHHHHHH HH

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Macromolecule #3: Isoform 5 of Interleukin-17 receptor C

MacromoleculeName: Isoform 5 of Interleukin-17 receptor C / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.294309 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LERLVGPQDA THCSPGLSCR LWDSDILCLP GDIVPAPGPV LAPTHLQTEL VLRCQKETDC DLCLRVAVHL AVHGHWEEPE DEEKFGGAA DLGVEEPRNA SLQAQVVLSF QAYPTARCVL LEVQVPAALV QFGQSVGSVV YDCFEAALGS EVRIWSYTQP R YEKELNHT ...String:
LERLVGPQDA THCSPGLSCR LWDSDILCLP GDIVPAPGPV LAPTHLQTEL VLRCQKETDC DLCLRVAVHL AVHGHWEEPE DEEKFGGAA DLGVEEPRNA SLQAQVVLSF QAYPTARCVL LEVQVPAALV QFGQSVGSVV YDCFEAALGS EVRIWSYTQP R YEKELNHT QQLPDCRGLE VWNSIPSCWA LPWLNVSADG DNVHLVLNVS EEQHFGLSLY WNQVQGPPKP RWHKNLTGPQ II TLNHTDL VPCLCIQVWP LEPDSVRTNI CPFREDPRAH QNLWQAARLR LLTLQSWLLD APCSLPAEAA LCWRAPGGDP CQP LVPPLS WENVTVDKVL EFPLLKGHPN LCVQVNSSEK LQLQECLWAD SLGPLKDDVL LLETRGPQDN RSLCALEPSG CTSL PSKAS TRAARLGEYL LQDLQSGQCL QLWDDDLGAL WACPMDKYIH AAALEVLFQG PGAAEDQVDP RLIDGKHHHH HHHH

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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: 9 / 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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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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
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (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

Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 542344
FSC plot (resolution estimation)

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