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- EMDB-38308: LGR4-RSPO2-ZNRF3 RING domain (1:2:2) -

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Basic information

Entry
Database: EMDB / ID: EMD-38308
TitleLGR4-RSPO2-ZNRF3 RING domain (1:2:2)
Map data
Sample
  • Complex: the pentamer B complex of LGR4-RSPO2-ZNRF3(RING)
    • Protein or peptide: Leucine-rich repeat-containing G-protein coupled receptor 4
    • Protein or peptide: E3 ubiquitin-protein ligase ZNRF3
    • Protein or peptide: nanobody Nb52
    • Protein or peptide: R-spondin-2
Keywordslgr4 / znrf3 RING domain / 1:2:2 / MEMBRANE PROTEIN
Function / homology
Function and homology information


trachea cartilage morphogenesis / negative regulation of odontogenesis of dentin-containing tooth / lung growth / regulation of Wnt signaling pathway, planar cell polarity pathway / Wnt receptor catabolic process / metanephric glomerulus development / metanephric nephron tubule morphogenesis / negative regulation of non-canonical Wnt signaling pathway / Regulation of FZD by ubiquitination / epithelial cell proliferation involved in renal tubule morphogenesis ...trachea cartilage morphogenesis / negative regulation of odontogenesis of dentin-containing tooth / lung growth / regulation of Wnt signaling pathway, planar cell polarity pathway / Wnt receptor catabolic process / metanephric glomerulus development / metanephric nephron tubule morphogenesis / negative regulation of non-canonical Wnt signaling pathway / Regulation of FZD by ubiquitination / epithelial cell proliferation involved in renal tubule morphogenesis / protein-hormone receptor activity / intestinal stem cell homeostasis / negative regulation of toll-like receptor signaling pathway / positive regulation of branching involved in ureteric bud morphogenesis / male genitalia development / bone remodeling / dopaminergic neuron differentiation / frizzled binding / embryonic forelimb morphogenesis / embryonic hindlimb morphogenesis / digestive tract development / limb development / negative regulation of cold-induced thermogenesis / negative regulation of cytokine production / epithelial tube branching involved in lung morphogenesis / bone mineralization / hair follicle development / canonical Wnt signaling pathway / Regulation of FZD by ubiquitination / stem cell proliferation / circadian regulation of gene expression / negative regulation of canonical Wnt signaling pathway / G protein-coupled receptor activity / RING-type E3 ubiquitin transferase / Wnt signaling pathway / ubiquitin-protein transferase activity / osteoblast differentiation / ubiquitin protein ligase activity / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / heparin binding / ubiquitin-dependent protein catabolic process / spermatogenesis / protein ubiquitination / signaling receptor binding / innate immune response / cell surface / extracellular region / zinc ion binding / plasma membrane
Similarity search - Function
Spondin-like TSP1 domain / Spondin-like TSP1 domain / E3 ubiquitin-protein ligase ZNRF3, Zinc finger, RING-type / ZNRF-3, ectodomain / ZNRF-3 Ectodomain / : / R-spondin, Fu-CRD domain / : / Furin-like repeat, cysteine-rich / Glycoprotein hormone receptor family ...Spondin-like TSP1 domain / Spondin-like TSP1 domain / E3 ubiquitin-protein ligase ZNRF3, Zinc finger, RING-type / ZNRF-3, ectodomain / ZNRF-3 Ectodomain / : / R-spondin, Fu-CRD domain / : / Furin-like repeat, cysteine-rich / Glycoprotein hormone receptor family / Ring finger domain / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Thrombospondin type-1 (TSP1) repeat superfamily / Thrombospondin type-1 (TSP1) repeat profile. / Thrombospondin type 1 repeats / Thrombospondin type-1 (TSP1) repeat / Leucine Rich Repeat / Leucine-rich repeats, bacterial type / Leucine-rich repeat, SDS22-like subfamily / Furin-like repeat / Furin-like repeats / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Ring finger / Growth factor receptor cysteine-rich domain superfamily / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
R-spondin-2 / Leucine-rich repeat-containing G-protein coupled receptor 4 / E3 ubiquitin-protein ligase ZNRF3
Similarity search - Component
Biological speciesHomo sapiens (human) / Camelus bactrianus (Bactrian camel)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLu W / Yong G
Funding support China, 1 items
OrganizationGrant numberCountry
Not funded China
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling.
Authors: Lu Wang / Fangzheng Hu / Qianqian Cui / Huarui Qiao / Lingyun Li / Tengjie Geng / Yuying Li / Zengchao Sun / Siyu Zhou / Zhongyun Lan / Shaojue Guo / Ying Hu / Jiqiu Wang / Qilun Yang / ...Authors: Lu Wang / Fangzheng Hu / Qianqian Cui / Huarui Qiao / Lingyun Li / Tengjie Geng / Yuying Li / Zengchao Sun / Siyu Zhou / Zhongyun Lan / Shaojue Guo / Ying Hu / Jiqiu Wang / Qilun Yang / Zenan Wang / Yuanyuan Dai / Yong Geng /
Abstract: WNT/β-catenin signaling plays key roles in development and cancer. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening WNT/β-catenin signaling. Conversely, RSPO1-4 binding to LGR4-6 ...WNT/β-catenin signaling plays key roles in development and cancer. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening WNT/β-catenin signaling. Conversely, RSPO1-4 binding to LGR4-6 and ZNRF3/RNF43 enhances WNT/β-catenin signaling. Here, we elucidate the overall landscape of architectures in multiple LGR4, RSPO2, and ZNRF3 assemblies, showcasing varying stoichiometries and arrangements. These structures reveal that LGR4 and RSPO2 capture distinct states of ZNRF3. The intrinsic heterogeneity of the LGR4-RSPO2-ZNRF3 assembly is influenced by LGR4 content. Particularly, in the assembly complex with a 2:2:2 ratio, two LGR4 protomers induce and stabilize the inactive state of ZNRF3, characterized by a wide inward-open conformation of two transmembrane helices (TM helices). This specific assembly promotes a stable complex, facilitating LGR4-induced endocytosis of ZNRF3. In contrast, the active dimeric ZNRF3, bound by a single LGR4, adopts a coiled-coil TM helices conformation and dimerization of RING domains. Our findings unveil how LGR4 content mediates diverse assemblies, leading to conformational rearrangements in ZNRF3 to regulate WNT/β-catenin signaling, and provide a structural foundation for drug development targeting Wnt-driven cancers.
History
DepositionDec 14, 2023-
Header (metadata) releaseDec 4, 2024-
Map releaseDec 4, 2024-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38308.png

Downloads & links

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Map

FileDownload / File: emd_38308.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 512 pix.
= 548.352 Å		1.07 Å/pix.
x 512 pix.
= 548.352 Å		1.07 Å/pix.
x 512 pix.
= 548.352 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.16
Minimum - Maximum-0.73962843 - 1.2511574
Average (Standard dev.)-0.00028746462 (±0.01856504)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 548.352 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38308_half_map_1.map
Projections & Slices
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Slices (1/2)
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Histogram

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Half map: #1

Fileemd_38308_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : the pentamer B complex of LGR4-RSPO2-ZNRF3(RING)

EntireName: the pentamer B complex of LGR4-RSPO2-ZNRF3(RING)
Components
  • Complex: the pentamer B complex of LGR4-RSPO2-ZNRF3(RING)
    • Protein or peptide: Leucine-rich repeat-containing G-protein coupled receptor 4
    • Protein or peptide: E3 ubiquitin-protein ligase ZNRF3
    • Protein or peptide: nanobody Nb52
    • Protein or peptide: R-spondin-2

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Supramolecule #1: the pentamer B complex of LGR4-RSPO2-ZNRF3(RING)

SupramoleculeName: the pentamer B complex of LGR4-RSPO2-ZNRF3(RING) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Leucine-rich repeat-containing G-protein coupled receptor 4

MacromoleculeName: Leucine-rich repeat-containing G-protein coupled receptor 4
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.483367 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: APCSCDGDRR VDCSGKGLTA VPEGLSAFTQ ALDISMNNIT QLPEDAFANF PFLEELQLAG NDLSFIHPKA LSGLKELKVL TLQNNQLKT VPSEAIRGLS ALQSLRLDAN HITSVPEDSF EGLVQLRHLW LDDNSLTEVP VHPLSNLPTL QALTLALNKI S SIPDFAFT ...String:
APCSCDGDRR VDCSGKGLTA VPEGLSAFTQ ALDISMNNIT QLPEDAFANF PFLEELQLAG NDLSFIHPKA LSGLKELKVL TLQNNQLKT VPSEAIRGLS ALQSLRLDAN HITSVPEDSF EGLVQLRHLW LDDNSLTEVP VHPLSNLPTL QALTLALNKI S SIPDFAFT NLSSLVVLHL HNNKIRSLSQ HCFDGLDNLE TLDLNYNNLG EFPQAIKALP SLKELGFHSN SISVIPDGAF DG NPLLRTI HLYDNPLSFV GNSAFHNLSD LHSLVIRGAS MVQQFPNLTG TVHLESLTLT GTKISSIPNN LCQEQKMLRT LDL SYNNIR DLPSFNGCHA LEEISLQRNQ IYQIKEGTFQ GLISLRILDL SRNLIHEIHS RAFATLGPIT NLDVSFNELT SFPT EGLNG LNQLKLVGNF KLKEALAAKD FVNLRSLSVP YAYQCCAFWG CDSYANLNTE DNSLQDHSVA QEKGTADAAN VTSTL ENEE HSQIIIHCTP STGAFKPCEY LLGSWMIRLT VWFIFLVALF FNLLVILTTF ASCTSLPSSK LFIGLISVSN LFMGIY TGI LTFLDAVSWG RFAEFGIWWE TGSGCKVAGF LAVFSSESAI FLLMLATVER SLSAKDIMKN GKSNHLKQFR VAALLAF LG ATVAGCFPLF HRGEYSASPL CLPFPTGETP SLGFTVTLVL LNSLAFLLMA VIYTKLYCNL EKEDLSENSQ SSMIKHVA W LIFTNCIFFC PVAFFSFAPL ITAISISPEI MKSVTLIFFP LPACLNPVLY VFFNPKFKED WKLLKRRVTK

UniProtKB: Leucine-rich repeat-containing G-protein coupled receptor 4

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Macromolecule #2: E3 ubiquitin-protein ligase ZNRF3

MacromoleculeName: E3 ubiquitin-protein ligase ZNRF3 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.149381 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
KETAFVEVVL FESSPSGDYT TYTTGLTGRF SRAGATLSAE GEIVQMHPLG LCNNNDEEDL YEYGWVGVVK LEQPELDPKP CLTVLGKAK RAVQRGATAV IFDVSENPEA IDQLNQGSED PLKRPVVYVK GADAIKLMNI VNKQKVARAR IQHRPPRQPT E YFDMGIFL AFFVVVSLVC LILLVKIKLK QR

UniProtKB: E3 ubiquitin-protein ligase ZNRF3

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Macromolecule #3: nanobody Nb52

MacromoleculeName: nanobody Nb52 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Camelus bactrianus (Bactrian camel)
Molecular weightTheoretical: 11.673085 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SLRLSCAASG YTYSPYCMGW FRQAPGKARE GVATVDLDGS TIYADSVKGR FTISQDNAKN TLYLQMNSLK PEDTAMYYCA SRTRAGVTC GLNWAIFSYW GQGTQVT

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Macromolecule #4: R-spondin-2

MacromoleculeName: R-spondin-2 / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.67543 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
KGCLSCSKDN GCSRCQQKLF FFLRREGMRQ YGECLHSCPS GYYGHRAPDM NRCARCRIEN CDSCFSKDFC TKCKVGFYLH RGRCFDECP DGFAPLDETM EC

UniProtKB: R-spondin-2

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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

MicroscopeFEI TECNAI 20
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.944 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 61066
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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