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- PDB-8xfs: LGR4-RSPO2-ZNRF3 RING domain (1:2:2) -

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Basic information

Entry
Database: PDB / ID: 8xfs
TitleLGR4-RSPO2-ZNRF3 RING domain (1:2:2)
Components
  • E3 ubiquitin-protein ligase ZNRF3
  • Leucine-rich repeat-containing G-protein coupled receptor 4
  • R-spondin-2
  • nanobody Nb52
KeywordsMEMBRANE PROTEIN / lgr4 / znrf3 RING domain / 1:2:2
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLu, W. / Yong, G.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 4, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Leucine-rich repeat-containing G-protein coupled receptor 4
C: E3 ubiquitin-protein ligase ZNRF3
F: nanobody Nb52
B: R-spondin-2
E: E3 ubiquitin-protein ligase ZNRF3
D: R-spondin-2


Theoretical massNumber of molelcules
Total (without water)164,8066
Polymers164,8066
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Leucine-rich repeat-containing G-protein coupled receptor 4 / G-protein coupled receptor 48


Mass: 87483.367 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LGR4, GPR48 / Production host: Homo sapiens (human) / References: UniProt: Q9BXB1
#2: Protein E3 ubiquitin-protein ligase ZNRF3 / RING finger protein 203 / RING-type E3 ubiquitin transferase ZNRF3 / Zinc/RING finger protein 3


Mass: 21149.381 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ZNRF3, KIAA1133, RNF203 / Production host: Homo sapiens (human)
References: UniProt: Q9ULT6, RING-type E3 ubiquitin transferase
#3: Antibody nanobody Nb52


Mass: 11673.085 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Camelus bactrianus (Bactrian camel) / Production host: Escherichia coli (E. coli)
#4: Protein R-spondin-2 / Cysteine-rich and single thrombospondin domain-containing protein 2 / Cristin-2 / mCristin-2 / Roof ...Cysteine-rich and single thrombospondin domain-containing protein 2 / Cristin-2 / mCristin-2 / Roof plate-specific spondin-2


Mass: 11675.430 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: Rspo2 / Production host: Homo sapiens (human) / References: UniProt: Q8BFU0
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: the pentamer B complex of LGR4-RSPO2-ZNRF3(RING) / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TECNAI 20
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 1.944 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 61066 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00211229
ELECTRON MICROSCOPYf_angle_d0.50615227
ELECTRON MICROSCOPYf_dihedral_angle_d10.3054056
ELECTRON MICROSCOPYf_chiral_restr0.041731
ELECTRON MICROSCOPYf_plane_restr0.0031954

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