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Protein

E3 ubiquitin-protein ligase ZNRF3

Gene

ZNRF3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby resticting the size of the intestinal stem cell zone.1 Publication

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[acceptor protein]-L-lysine.

Enzyme regulationi

Negatively regulated by R-spondin proteins such as RSPO1: interaction with RSPO1 induces the indirect association between ZNRF3 and LGR4, promoting membrane clearance of ZNRF3.1 Publication

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri293 – 334RING-type; atypicalPROSITE-ProRule annotationAdd BLAST42

GO - Molecular functioni

  • frizzled binding Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • ubiquitin protein ligase activity Source: ParkinsonsUK-UCL
  • ubiquitin-protein transferase activity Source: UniProtKB

GO - Biological processi

  • canonical Wnt signaling pathway Source: Ensembl
  • negative regulation of canonical Wnt signaling pathway Source: UniProtKB
  • negative regulation of non-canonical Wnt signaling pathway Source: UniProtKB
  • protein ubiquitination Source: UniProtKB
  • stem cell proliferation Source: UniProtKB
  • ubiquitin-dependent protein catabolic process Source: UniProtKB
  • Wnt receptor catabolic process Source: UniProtKB
  • Wnt signaling pathway, planar cell polarity pathway Source: Ensembl

Keywordsi

Molecular functionTransferase
Biological processUbl conjugation pathway, Wnt signaling pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-4641263 Regulation of FZD by ubiquitination
SIGNORiQ9ULT6
UniPathwayiUPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase ZNRF3 (EC:2.3.2.27)
Alternative name(s):
RING finger protein 203
RING-type E3 ubiquitin transferase ZNRF3
Zinc/RING finger protein 3
Gene namesi
Name:ZNRF3
Synonyms:KIAA1133, RNF203
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 22

Organism-specific databases

EuPathDBiHostDB:ENSG00000183579.15
HGNCiHGNC:18126 ZNRF3
MIMi612062 gene
neXtProtiNX_Q9ULT6

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini56 – 219ExtracellularSequence analysisAdd BLAST164
Transmembranei220 – 240HelicalSequence analysisAdd BLAST21
Topological domaini241 – 936CytoplasmicSequence analysisAdd BLAST696

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi103P → A: Abolishes interaction with RSPO1 and prevents subsequent membrane clearance. 1 Publication1

Organism-specific databases

DisGeNETi84133
OpenTargetsiENSG00000183579
PharmGKBiPA134983897

Polymorphism and mutation databases

BioMutaiZNRF3
DMDMi126253847

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 55Sequence analysisAdd BLAST55
ChainiPRO_000027780656 – 936E3 ubiquitin-protein ligase ZNRF3Add BLAST881

Proteomic databases

EPDiQ9ULT6
PaxDbiQ9ULT6
PeptideAtlasiQ9ULT6
PRIDEiQ9ULT6
ProteomicsDBi85106
85107 [Q9ULT6-2]

PTM databases

iPTMnetiQ9ULT6
PhosphoSitePlusiQ9ULT6

Expressioni

Gene expression databases

BgeeiENSG00000183579
CleanExiHS_ZNRF3
ExpressionAtlasiQ9ULT6 baseline and differential
GenevisibleiQ9ULT6 HS

Organism-specific databases

HPAiHPA036702
HPA036703

Interactioni

Subunit structurei

Interacts with LRP6, FZD4, FZD5, FZD6 and FZD8. Interacts with RSPO1; interaction promotes indirect interaction with LGR4 and membrane clearance of ZNRF3.1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • frizzled binding Source: UniProtKB

Protein-protein interaction databases

BioGridi123905, 14 interactors
DIPiDIP-50030N
IntActiQ9ULT6, 8 interactors
MINTiQ9ULT6
STRINGi9606.ENSP00000443824

Structurei

3D structure databases

ProteinModelPortaliQ9ULT6
SMRiQ9ULT6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the ZNRF3 family.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri293 – 334RING-type; atypicalPROSITE-ProRule annotationAdd BLAST42

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix, Zinc-finger

Phylogenomic databases

eggNOGiKOG0800 Eukaryota
ENOG41121N2 LUCA
GeneTreeiENSGT00760000119057
HOGENOMiHOG000155811
HOVERGENiHBG082538
InParanoidiQ9ULT6
KOiK16273
OMAiGCYTEDY
OrthoDBiEOG091G01HM
PhylomeDBiQ9ULT6
TreeFamiTF317074

Family and domain databases

Gene3Di3.30.40.10, 1 hit
InterProiView protein in InterPro
IPR001841 Znf_RING
IPR013083 Znf_RING/FYVE/PHD
PfamiView protein in Pfam
PF13639 zf-RING_2, 1 hit
SMARTiView protein in SMART
SM00184 RING, 1 hit
PROSITEiView protein in PROSITE
PS50089 ZF_RING_2, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9ULT6-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MRPRSGGRPG ATGRRRRRLR RRPRGLRCSR LPPPPPLPLL LGLLLAAAGP
60 70 80 90 100
GAARAKETAF VEVVLFESSP SGDYTTYTTG LTGRFSRAGA TLSAEGEIVQ
110 120 130 140 150
MHPLGLCNNN DEEDLYEYGW VGVVKLEQPE LDPKPCLTVL GKAKRAVQRG
160 170 180 190 200
ATAVIFDVSE NPEAIDQLNQ GSEDPLKRPV VYVKGADAIK LMNIVNKQKV
210 220 230 240 250
ARARIQHRPP RQPTEYFDMG IFLAFFVVVS LVCLILLVKI KLKQRRSQNS
260 270 280 290 300
MNRLAVQALE KMETRKFNSK SKGRREGSCG ALDTLSSSST SDCAICLEKY
310 320 330 340 350
IDGEELRVIP CTHRFHRKCV DPWLLQHHTC PHCRHNIIEQ KGNPSAVCVE
360 370 380 390 400
TSNLSRGRQQ RVTLPVHYPG RVHRTNAIPA YPTRTSMDSH GNPVTLLTMD
410 420 430 440 450
RHGEQSLYSP QTPAYIRSYP PLHLDHSLAA HRCGLEHRAY SPAHPFRRPK
460 470 480 490 500
LSGRSFSKAA CFSQYETMYQ HYYFQGLSYP EQEGQSPPSL APRGPARAFP
510 520 530 540 550
PSGSGSLLFP TVVHVAPPSH LESGSTSSFS CYHGHRSVCS GYLADCPGSD
560 570 580 590 600
SSSSSSSGQC HCSSSDSVVD CTEVSNQGVY GSCSTFRSSL SSDYDPFIYR
610 620 630 640 650
SRSPCRASEA GGSGSSGRGP ALCFEGSPPP EELPAVHSHG AGRGEPWPGP
660 670 680 690 700
ASPSGDQVST CSLEMNYSSN SSLEHRGPNS STSEVGLEAS PGAAPDLRRT
710 720 730 740 750
WKGGHELPSC ACCCEPQPSP AGPSAGAAGS STLFLGPHLY EGSGPAGGEP
760 770 780 790 800
QSGSSQGLYG LHPDHLPRTD GVKYEGLPCC FYEEKQVARG GGGGSGCYTE
810 820 830 840 850
DYSVSVQYTL TEEPPPGCYP GARDLSQRIP IIPEDVDCDL GLPSDCQGTH
860 870 880 890 900
SLGSWGGTRG PDTPRPHRGL GATREEERAL CCQARALLRP GCPPEEAGAV
910 920 930
RANFPSALQD TQESSTTATE AAGPRSHSAD SSSPGA
Length:936
Mass (Da):100,574
Last modified:February 20, 2007 - v3
Checksum:iEE68B810BD3C9C74
GO
Isoform 2 (identifier: Q9ULT6-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-100: Missing.

Note: No experimental confirmation available.
Show »
Length:836
Mass (Da):89,908
Checksum:iFFA1207940602B17
GO

Sequence cautioni

The sequence CAG30283 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0440431 – 100Missing in isoform 2. CuratedAdd BLAST100

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK096397 mRNA Translation: BAG53280.1
Z95113 Genomic DNA No translation available.
AL021393 Genomic DNA No translation available.
AL031596 Genomic DNA No translation available.
AB051436 mRNA Translation: BAB33319.1
CR456397 mRNA Translation: CAG30283.1 Different initiation.
BC021570 mRNA Translation: AAH21570.1
BC069019 mRNA Translation: AAH69019.1
BC094857 mRNA Translation: AAH94857.1
CCDSiCCDS42999.1 [Q9ULT6-2]
CCDS56225.1 [Q9ULT6-1]
RefSeqiNP_001193927.1, NM_001206998.1 [Q9ULT6-1]
NP_115549.2, NM_032173.3 [Q9ULT6-2]
UniGeneiHs.604200
Hs.655242
Hs.732114

Genome annotation databases

EnsembliENST00000402174; ENSP00000384456; ENSG00000183579 [Q9ULT6-2]
ENST00000406323; ENSP00000384553; ENSG00000183579 [Q9ULT6-2]
ENST00000544604; ENSP00000443824; ENSG00000183579 [Q9ULT6-1]
GeneIDi84133
KEGGihsa:84133
UCSCiuc003aeg.4 human [Q9ULT6-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiZNRF3_HUMAN
AccessioniPrimary (citable) accession number: Q9ULT6
Secondary accession number(s): B3KU18
, Q6ICH1, Q6NTF8, Q8WU18
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 20, 2007
Last sequence update: February 20, 2007
Last modified: June 20, 2018
This is version 133 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 22
    Human chromosome 22: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  4. SIMILARITY comments
    Index of protein domains and families

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