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- EMDB-27244: Cryo-EM map of detergent-solubilized human IL-6 signaling complex... -

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Basic information

Entry
Database: EMDB / ID: EMD-27244
TitleCryo-EM map of detergent-solubilized human IL-6 signaling complex with full extracellular domains
Map dataIL6 signaling complex main map
Sample
  • Complex: Human IL-6 in complex with IL-6R alpha and detergent-solubilized gp130
    • Protein or peptide: Soluble interleukin-6 receptor subunit alpha
    • Protein or peptide: Interleukin-6
    • Protein or peptide: Interleukin-6 receptor subunit beta
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


ciliary neurotrophic factor binding / positive regulation of interleukin-21 production / regulation of astrocyte activation / glucagon secretion / regulation of glucagon secretion / negative regulation of interleukin-1-mediated signaling pathway / hepatic immune response / oncostatin-M-mediated signaling pathway / ciliary neurotrophic factor receptor activity / negative regulation of interleukin-6-mediated signaling pathway ...ciliary neurotrophic factor binding / positive regulation of interleukin-21 production / regulation of astrocyte activation / glucagon secretion / regulation of glucagon secretion / negative regulation of interleukin-1-mediated signaling pathway / hepatic immune response / oncostatin-M-mediated signaling pathway / ciliary neurotrophic factor receptor activity / negative regulation of interleukin-6-mediated signaling pathway / leukemia inhibitory factor signaling pathway / interleukin-27 receptor activity / regulation of vascular endothelial growth factor production / oncostatin-M receptor complex / negative regulation of primary miRNA processing / ciliary neurotrophic factor receptor binding / interleukin-11 receptor activity / interleukin-11 binding / T follicular helper cell differentiation / interleukin-6 receptor activity / interleukin-6 binding / ciliary neurotrophic factor-mediated signaling pathway / germinal center B cell differentiation / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / regulation of microglial cell activation / interleukin-6 receptor complex / positive regulation of extracellular matrix disassembly / positive regulation of receptor signaling pathway via STAT / positive regulation of type B pancreatic cell apoptotic process / positive regulation of apoptotic DNA fragmentation / response to peptidoglycan / hepatocyte proliferation / neutrophil apoptotic process / interleukin-6 receptor binding / negative regulation of collagen biosynthetic process / positive regulation of activation of Janus kinase activity / interleukin-11-mediated signaling pathway / inflammatory response to wounding / T-helper 17 cell lineage commitment / positive regulation of T-helper 2 cell cytokine production / positive regulation of adaptive immune response / positive regulation of B cell activation / positive regulation of glomerular mesangial cell proliferation / endocrine pancreas development / negative regulation of interleukin-8 production / positive regulation of acute inflammatory response / regulation of neuroinflammatory response / vascular endothelial growth factor production / negative regulation of chemokine production / positive regulation of astrocyte differentiation / positive regulation of neuroinflammatory response / intestinal epithelial cell development / positive regulation of platelet aggregation / neutrophil mediated immunity / positive regulation of cytokine production involved in inflammatory response / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / negative regulation of bone resorption / positive regulation of leukocyte chemotaxis / positive regulation of leukocyte adhesion to vascular endothelial cell / CD163 mediating an anti-inflammatory response / cytokine receptor activity / positive regulation of immunoglobulin production / maintenance of blood-brain barrier / glycogen metabolic process / interleukin-6-mediated signaling pathway / Interleukin-6 signaling / positive regulation of Notch signaling pathway / negative regulation of fat cell differentiation / protein tyrosine kinase activator activity / positive regulation of cardiac muscle hypertrophy / cytokine binding / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / growth factor binding / Interleukin-10 signaling / monocyte chemotaxis / MAPK1 (ERK2) activation / regulation of insulin secretion / positive regulation of interleukin-10 production / humoral immune response / negative regulation of lipid storage / Transcriptional Regulation by VENTX / positive regulation of vascular endothelial growth factor production / regulation of angiogenesis / positive regulation of osteoblast differentiation / coreceptor activity / positive regulation of epithelial to mesenchymal transition / extrinsic apoptotic signaling pathway / positive regulation of T cell proliferation / positive regulation of chemokine production / response to glucocorticoid / positive regulation of glial cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / response to activity / positive regulation of interleukin-1 beta production / response to cytokine / cytokine activity
Similarity search - Function
Interleukin-6 / Interleukin-6/G-CSF/MGF family / Interleukin-6/GCSF/MGF, conserved site / Interleukin-6 / G-CSF / MGF signature. / Interleukin-6/GCSF/MGF / Interleukin-6 homologues / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain ...Interleukin-6 / Interleukin-6/G-CSF/MGF family / Interleukin-6/GCSF/MGF, conserved site / Interleukin-6 / G-CSF / MGF signature. / Interleukin-6/GCSF/MGF / Interleukin-6 homologues / 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. / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Four-helical cytokine-like, core / Immunoglobulin / Immunoglobulin domain / Fibronectin type III domain / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-6 / Interleukin-6 receptor subunit alpha / Interleukin-6 receptor subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsZhou Y / Franklin MC
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Sci Adv / Year: 2023
Title: Structural insights into the assembly of gp130 family cytokine signaling complexes.
Authors: Yi Zhou / Panayiotis E Stevis / Jing Cao / Kei Saotome / Jiaxi Wu / Arielle Glatman Zaretsky / Sokol Haxhinasto / George D Yancopoulos / Andrew J Murphy / Mark W Sleeman / William C Olson / Matthew C Franklin /
Abstract: The interleukin-6 (IL-6) family cytokines signal through gp130 receptor homodimerization or heterodimerization with a second signaling receptor and play crucial roles in various cellular processes. ...The interleukin-6 (IL-6) family cytokines signal through gp130 receptor homodimerization or heterodimerization with a second signaling receptor and play crucial roles in various cellular processes. We determined cryo-electron microscopy structures of five signaling complexes of this family, containing full receptor ectodomains bound to their respective ligands ciliary neurotrophic factor, cardiotrophin-like cytokine factor 1 (CLCF1), leukemia inhibitory factor, IL-27, and IL-6. Our structures collectively reveal similarities and differences in the assembly of these complexes. The acute bends at both signaling receptors in all complexes bring the membrane-proximal domains to a ~30 angstrom range but with distinct distances and orientations. We also reveal how CLCF1 engages its secretion chaperone cytokine receptor-like factor 1. Our data provide valuable insights for therapeutically targeting gp130-mediated signaling.
History
DepositionJun 7, 2022-
Header (metadata) releaseMar 29, 2023-
Map releaseMar 29, 2023-
UpdateMar 29, 2023-
Current statusMar 29, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27244.png

Downloads & links

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Map

FileDownload / File: emd_27244.map.gz / Format: CCP4 / Size: 361.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationIL6 signaling complex main map
Voxel sizeX=Y=Z: 0.85 Å
Density
Contour LevelBy AUTHOR: 0.085
Minimum - Maximum-0.6746953 - 1.2203913
Average (Standard dev.)0.00013123004 (±0.02317359)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions456456456
Spacing456456456
CellA=B=C: 387.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_27244_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_27244_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human IL-6 in complex with IL-6R alpha and detergent-solubilized gp130

EntireName: Human IL-6 in complex with IL-6R alpha and detergent-solubilized gp130
Components
  • Complex: Human IL-6 in complex with IL-6R alpha and detergent-solubilized gp130
    • Protein or peptide: Soluble interleukin-6 receptor subunit alpha
    • Protein or peptide: Interleukin-6
    • Protein or peptide: Interleukin-6 receptor subunit beta
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Human IL-6 in complex with IL-6R alpha and detergent-solubilized gp130

SupramoleculeName: Human IL-6 in complex with IL-6R alpha and detergent-solubilized gp130
type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Soluble interleukin-6 receptor subunit alpha

MacromoleculeName: Soluble interleukin-6 receptor subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.69432 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: LAPRRCPAQE VARGVLTSLP GDSVTLTCPG VEPEDNATVH WVLRKPAAGS HPSRWAGMGR RLLLRSVQLH DSGNYSCYRA GRPAGTVHL LVDVPPEEPQ LSCFRKSPLS NVVCEWGPRS TPSLTTKAVL LVRKFQNSPA EDFQEPCQYS QESQKFSCQL A VPEGDSSF ...String:
LAPRRCPAQE VARGVLTSLP GDSVTLTCPG VEPEDNATVH WVLRKPAAGS HPSRWAGMGR RLLLRSVQLH DSGNYSCYRA GRPAGTVHL LVDVPPEEPQ LSCFRKSPLS NVVCEWGPRS TPSLTTKAVL LVRKFQNSPA EDFQEPCQYS QESQKFSCQL A VPEGDSSF YIVSMCVASS VGSKFSKTQT FQGCGILQPD PPANITVTAV ARNPRWLSVT WQDPHSWNSS FYRLRFELRY RA ERSKTFT TWMVKDLQHH CVIHDAWSGL RHVVQLRAQE EFGQGEWSEW SPEAMGTPWT ESRSPPAENE VSTPMGPGGE QKL ISEEDL GGEQKLISEE DLSGHHHHHH

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Macromolecule #2: Interleukin-6

MacromoleculeName: Interleukin-6 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.83777 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
VPPGEDSKDV AAPHRQPLTS SERIDKQIRY ILDGISALRK ETCNKSNMCE SSKEALAENN LNLPKMAEKD GCFQSGFNEE TCLVKIITG LLEFEVYLEY LQNRFESSEE QARAVQMSTK VLIQFLQKKA KNLDAITTPD PTTNASLLTK LQAQNQWLQD M TTHLILRS FKEFLQSSLR ALRQM

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Macromolecule #3: Interleukin-6 receptor subunit beta

MacromoleculeName: Interleukin-6 receptor subunit beta / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 77.085125 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 ITYEDRPSKA PSFWYKIDPS HTQ GYRTVQ LVWKTLPPFE ANGKILDYEV TLTRWKSHLQ NYTVNATKLT VNLTNDRYLA TLTVRNLVGK SDAAVLTIPA CDFQ ATHPV MDLKAFPKDN MLWVEWTTPR ESVKKYILEW CVLSDKAPCI TDWQQEDGTV HRTYLRGNLA ESKCYLITVT PVYAD GPGS PESIKAYLKQ APPSKGPTVR TKKVGKNEAV LEWDQLPVDV QNGFIRNYTI FYRTIIGNET AVNVDSSHTE YTLSSL TSD TLYMVRMAAY TDEGGKDGPE FTFTTPKFAQ GEIEAIVVPV CLAFLLTTLL GVLFCFNKRD LIKKHIWPNV PDPSKSH IA QWSPHTPPRH NFNSKDQMYS DGNFTDVSVV EIEAND

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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: 18 / 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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.4000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 105760
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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