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- EMDB-27227: Cryo-EM map of human CNTF signaling complex with full extracellul... -

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Basic information

Entry
Database: EMDB / ID: EMD-27227
TitleCryo-EM map of human CNTF signaling complex with full extracellular domains: refined from selected full particle dataset, with better resolution in the interaction core region
Map dataHigher resolution map used for model building
Sample
  • Complex: Human CNTF in complex with CNTFR alpha, gp130, and LIFR
    • Protein or peptide: Interleukin-6 receptor subunit beta
    • Protein or peptide: Ciliary neurotrophic factor
    • Protein or peptide: Ciliary neurotrophic factor receptor subunit alpha
    • Protein or peptide: Leukemia inhibitory factor receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordscytokine signaling / CNTF / CNTFR alpha / gp130 / LIFR / CYTOKINE
Function / homology
Function and homology information


CNTFR-CLCF1 complex / skeletal muscle organ development / leukemia inhibitory factor receptor activity / oncostatin-M-mediated signaling pathway / regulation of retinal cell programmed cell death / interleukin-27 receptor activity / muscle organ morphogenesis / ciliary neurotrophic factor receptor activity / retinal rod cell differentiation / leukemia inhibitory factor signaling pathway ...CNTFR-CLCF1 complex / skeletal muscle organ development / leukemia inhibitory factor receptor activity / oncostatin-M-mediated signaling pathway / regulation of retinal cell programmed cell death / interleukin-27 receptor activity / muscle organ morphogenesis / ciliary neurotrophic factor receptor activity / retinal rod cell differentiation / leukemia inhibitory factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / oncostatin-M receptor complex / ciliary neurotrophic factor receptor binding / interleukin-11 receptor activity / interleukin-11 binding / RUNX1 regulates transcription of genes involved in interleukin signaling / ciliary neurotrophic factor-mediated signaling pathway / negative regulation of photoreceptor cell differentiation / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / interleukin-6 receptor complex / interleukin-6 receptor binding / brainstem development / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / sex differentiation / positive regulation of adaptive immune response / positive regulation of acute inflammatory response / positive regulation of astrocyte differentiation / intestinal epithelial cell development / negative regulation of motor neuron apoptotic process / positive regulation of platelet aggregation / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / cytokine receptor activity / motor neuron apoptotic process / extrinsic component of membrane / glycogen metabolic process / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / protein tyrosine kinase activator activity / suckling behavior / positive regulation of cardiac muscle hypertrophy / positive regulation of axon regeneration / MAPK3 (ERK1) activation / cytokine binding / growth factor binding / MAPK1 (ERK2) activation / positive regulation of vascular endothelial growth factor production / neuron development / positive regulation of osteoblast differentiation / coreceptor activity / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / response to cytokine / cytokine activity / astrocyte activation / growth factor activity / cytokine-mediated signaling pathway / nervous system development / scaffold protein binding / negative regulation of neuron apoptotic process / receptor complex / cell surface receptor signaling pathway / membrane raft / apical plasma membrane / axon / external side of plasma membrane / signaling receptor binding / neuronal cell body / dendrite / positive regulation of cell population proliferation / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / signal transduction / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Ciliary neurotrophic factor, CNTF / Ciliary neurotrophic factor / Leukemia inhibitory factor receptor, D2 domain / Leukemia inhibitory factor receptor, N-terminal / : / Leukemia inhibitory factor receptor D2 domain / Leukemia inhibitory factor receptor N-terminal domain / Leukemia inhibitory factor receptor, Ig-like domain / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding ...Ciliary neurotrophic factor, CNTF / Ciliary neurotrophic factor / Leukemia inhibitory factor receptor, D2 domain / Leukemia inhibitory factor receptor, N-terminal / : / Leukemia inhibitory factor receptor D2 domain / Leukemia inhibitory factor receptor N-terminal domain / Leukemia inhibitory factor receptor, Ig-like domain / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chain, conserved site / 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 / 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
Ciliary neurotrophic factor / Ciliary neurotrophic factor receptor subunit alpha / Interleukin-6 receptor subunit beta / Leukemia inhibitory factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.03 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-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27227.png

Downloads & links

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Map

FileDownload / File: emd_27227.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHigher resolution map used for model building
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 400 pix.
= 340. Å		0.85 Å/pix.
x 400 pix.
= 340. Å		0.85 Å/pix.
x 400 pix.
= 340. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.6451044 - 1.3849548
Average (Standard dev.)-0.00011796876 (±0.025387594)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 340.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map A

Fileemd_27227_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_27227_half_map_2.map
Annotationhalf map B
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 CNTF in complex with CNTFR alpha, gp130, and LIFR

EntireName: Human CNTF in complex with CNTFR alpha, gp130, and LIFR
Components
  • Complex: Human CNTF in complex with CNTFR alpha, gp130, and LIFR
    • Protein or peptide: Interleukin-6 receptor subunit beta
    • Protein or peptide: Ciliary neurotrophic factor
    • Protein or peptide: Ciliary neurotrophic factor receptor subunit alpha
    • Protein or peptide: Leukemia inhibitory factor receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Human CNTF in complex with CNTFR alpha, gp130, and LIFR

SupramoleculeName: Human CNTF in complex with CNTFR alpha, gp130, and LIFR
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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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: Homo sapiens (human)
Molecular weightTheoretical: 71.233203 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
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 GEIEEQKLIS EEDLGGEQKL ISEEDLHHHH HH

UniProtKB: Interleukin-6 receptor subunit beta

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Macromolecule #2: Ciliary neurotrophic factor

MacromoleculeName: Ciliary neurotrophic factor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.704854 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: MAFTEHSPLT PHRRDLCSRS IWLARKIRSD LTALTESYVK HQGLNKNINL DSADGMPVAS TDQWSELTEA ERLQENLQAY RTFHVLLAR LLEDQQVHFT PTEGDFHQAI HTLLLQVAAF AYQIEELMIL LEYKIPRNEA DGMPINVGDG GLFEKKLWGL K VLQELSQW ...String:
MAFTEHSPLT PHRRDLCSRS IWLARKIRSD LTALTESYVK HQGLNKNINL DSADGMPVAS TDQWSELTEA ERLQENLQAY RTFHVLLAR LLEDQQVHFT PTEGDFHQAI HTLLLQVAAF AYQIEELMIL LEYKIPRNEA DGMPINVGDG GLFEKKLWGL K VLQELSQW TVRSIHDLRF ISSHQTGIEQ KLISEEDLGG EQKLISEEDL HHHHHH

UniProtKB: Ciliary neurotrophic factor

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Macromolecule #3: Ciliary neurotrophic factor receptor subunit alpha

MacromoleculeName: Ciliary neurotrophic factor receptor subunit alpha / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.855305 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QRHSPQEAPH VQYERLGSDV TLPCGTANWD AAVTWRVNGT DLAPDLLNGS QLVLHGLELG HSGLYACFHR DSWHLRHQVL LHVGLPPRE PVLSCRSNTY PKGFYCSWHL PTPTYIPNTF NVTVLHGSKI MVCEKDPALK NRCHIRYMHL FSTIKYKVSI S VSNALGHN ...String:
QRHSPQEAPH VQYERLGSDV TLPCGTANWD AAVTWRVNGT DLAPDLLNGS QLVLHGLELG HSGLYACFHR DSWHLRHQVL LHVGLPPRE PVLSCRSNTY PKGFYCSWHL PTPTYIPNTF NVTVLHGSKI MVCEKDPALK NRCHIRYMHL FSTIKYKVSI S VSNALGHN ATAITFDEFT IVKPDPPENV VARPVPSNPR RLEVTWQTPS TWPDPESFPL KFFLRYRPLI LDQWQHVELS DG TAHTITD AYAGKEYIIQ VAAKDNEIGT WSDWSVAAHA TPWTEEPRHL TTEAQAAETT TSTTSSLAPP PTTKICDPGE LGS

UniProtKB: Ciliary neurotrophic factor receptor subunit alpha

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Macromolecule #4: Leukemia inhibitory factor receptor

MacromoleculeName: Leukemia inhibitory factor receptor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 92.834812 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QKKGAPHDLK CVTNNLQVWN CSWKAPSGTG RGTDYEVCIE NRSRSCYQLE KTSIKIPALS HGDYEITINS LHDFGSSTSK FTLNEQNVS LIPDTPEILN LSADFSTSTL YLKWNDRGSV FPHRSNVIWE IKVLRKESME LVKLVTHNTT LNGKDTLHHW S WASDMPLE ...String:
QKKGAPHDLK CVTNNLQVWN CSWKAPSGTG RGTDYEVCIE NRSRSCYQLE KTSIKIPALS HGDYEITINS LHDFGSSTSK FTLNEQNVS LIPDTPEILN LSADFSTSTL YLKWNDRGSV FPHRSNVIWE IKVLRKESME LVKLVTHNTT LNGKDTLHHW S WASDMPLE CAIHFVEIRC YIDNLHFSGL EEWSDWSPVK NISWIPDSQT KVFPQDKVIL VGSDITFCCV SQEKVLSALI GH TNCPLIH LDGENVAIKI RNISVSASSG TNVVFTTEDN IFGTVIFAGY PPDTPQQLNC ETHDLKEIIC SWNPGRVTAL VGP RATSYT LVESFSGKYV RLKRAEAPTN ESYQLLFQML PNQEIYNFTL NAHNPLGRSQ STILVNITEK VYPHTPTSFK VKDI NSTAV KLSWHLPGNF AKINFLCEIE IKKSNSVQEQ RNVTIKGVEN SSYLVALDKL NPYTLYTFRI RCSTETFWKW SKWSN KKQH LTTEASPSKG PDTWREWSSD GKNLIIYWKP LPINEANGKI LSYNVSCSSD EETQSLSEIP DPQHKAEIRL DKNDYI ISV VAKNSVGSSP PSKIASMEIP NDDLKIEQVV GMGKGILLTW HYDPNMTCDY VIKWCNSSRS EPCLMDWRKV PSNSTET VI ESDEFRPGIR YNFFLYGCRN QGYQLLRSMI GYIEELAPIV APNFTVEDTS ADSILVKWED IPVEELRGFL RGYLFYFG K GERDTSKMRV LESGRSDIKV KNITDISQKT LRIADLQGKT SYHLVLRAYT DGGVGPEKSM YVVTKENSEQ KLISEEDLG GEQKLISEED LHHHHHH

UniProtKB: Leukemia inhibitory factor receptor

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 6 / 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

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 250735
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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