ZNRF1_HUMAN
ID ZNRF1_HUMAN Reviewed; 227 AA.
AC Q8ND25; D3DUJ9; Q9H083;
DT 20-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 20-FEB-2007, sequence version 2.
DT 03-AUG-2022, entry version 149.
DE RecName: Full=E3 ubiquitin-protein ligase ZNRF1;
DE EC=2.3.2.27;
DE AltName: Full=Nerve injury-induced gene 283 protein;
DE AltName: Full=RING-type E3 ubiquitin transferase ZNRF1;
DE AltName: Full=Zinc/RING finger protein 1;
GN Name=ZNRF1; Synonyms=NIN283;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX PubMed=11427537; DOI=10.1074/jbc.m104271200;
RA Araki T., Nagarajan R., Milbrandt J.;
RT "Identification of genes induced in peripheral nerve after injury.
RT Expression profiling and novel gene discovery.";
RL J. Biol. Chem. 276:34131-34141(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 8-278 (ISOFORM 2).
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, TISSUE SPECIFICITY, MYRISTOYLATION AT GLY-2, AND MUTAGENESIS OF
RP CYS-184.
RX PubMed=14561866; DOI=10.1523/jneurosci.23-28-09385.2003;
RA Araki T., Milbrandt J.;
RT "ZNRF proteins constitute a family of presynaptic E3 ubiquitin ligases.";
RL J. Neurosci. 23:9385-9394(2003).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-52 AND SER-53, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-123, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates the ubiquitination
CC of AKT1 and GLUL, thereby playing a role in neuron cells
CC differentiation. Plays a role in the establishment and maintenance of
CC neuronal transmission and plasticity. Regulates Schwann cells
CC differentiation by mediating ubiquitination of GLUL. Promotes
CC neurodegeneration by mediating 'Lys-48'-linked polyubiquitination and
CC subsequent degradation of AKT1 in axons: degradation of AKT1 prevents
CC AKT1-mediated phosphorylation of GSK3B, leading to GSK3B activation and
CC phosphorylation of DPYSL2/CRMP2 followed by destabilization of
CC microtubule assembly in axons (Probable).
CC {ECO:0000305|PubMed:14561866}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27;
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with AKT1, GLUL and TUBB2A. {ECO:0000250}.
CC -!- INTERACTION:
CC Q8ND25; P51668: UBE2D1; NbExp=9; IntAct=EBI-2129250, EBI-743540;
CC Q8ND25; P62837: UBE2D2; NbExp=7; IntAct=EBI-2129250, EBI-347677;
CC Q8ND25; P61077: UBE2D3; NbExp=3; IntAct=EBI-2129250, EBI-348268;
CC Q8ND25; Q9Y2X8: UBE2D4; NbExp=6; IntAct=EBI-2129250, EBI-745527;
CC Q8ND25; P51965: UBE2E1; NbExp=3; IntAct=EBI-2129250, EBI-348546;
CC Q8ND25; P61088: UBE2N; NbExp=4; IntAct=EBI-2129250, EBI-1052908;
CC Q8ND25; Q13404: UBE2V1; NbExp=2; IntAct=EBI-2129250, EBI-1050671;
CC Q8ND25; O94888: UBXN7; NbExp=5; IntAct=EBI-2129250, EBI-1993627;
CC -!- SUBCELLULAR LOCATION: Endosome. Lysosome. Membrane; Peripheral membrane
CC protein. Cytoplasmic vesicle, secretory vesicle, synaptic vesicle
CC membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}.
CC Note=Associated with synaptic vesicle membranes in neurons.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8ND25-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8ND25-2; Sequence=VSP_023088;
CC -!- TISSUE SPECIFICITY: Expressed primarily in the nervous system, with
CC expression higher in developing brain relative to adult. Expressed at
CC low levels in testis and thymus. {ECO:0000269|PubMed:11427537,
CC ECO:0000269|PubMed:14561866}.
CC -!- DOMAIN: The RING-type zinc finger domain is required for E3 ligase
CC activity. {ECO:0000250}.
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DR EMBL; AF378524; AAK69753.1; -; mRNA.
DR EMBL; AL136903; CAB66837.1; -; mRNA.
DR EMBL; AL834440; CAD39100.1; -; mRNA.
DR EMBL; AC092383; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC099508; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471114; EAW95668.1; -; Genomic_DNA.
DR EMBL; CH471114; EAW95670.1; -; Genomic_DNA.
DR EMBL; CH471114; EAW95671.1; -; Genomic_DNA.
DR EMBL; BC007235; AAH07235.1; -; mRNA.
DR CCDS; CCDS10912.1; -. [Q8ND25-1]
DR RefSeq; NP_115644.1; NM_032268.4. [Q8ND25-1]
DR RefSeq; XP_016879282.1; XM_017023793.1. [Q8ND25-1]
DR PDB; 5YWR; X-ray; 1.47 A; B=139-227.
DR PDBsum; 5YWR; -.
DR AlphaFoldDB; Q8ND25; -.
DR SMR; Q8ND25; -.
DR BioGRID; 124371; 34.
DR IntAct; Q8ND25; 17.
DR STRING; 9606.ENSP00000335091; -.
DR iPTMnet; Q8ND25; -.
DR PhosphoSitePlus; Q8ND25; -.
DR BioMuta; ZNRF1; -.
DR DMDM; 126253846; -.
DR EPD; Q8ND25; -.
DR jPOST; Q8ND25; -.
DR MassIVE; Q8ND25; -.
DR MaxQB; Q8ND25; -.
DR PaxDb; Q8ND25; -.
DR PeptideAtlas; Q8ND25; -.
DR PRIDE; Q8ND25; -.
DR ProteomicsDB; 72976; -. [Q8ND25-1]
DR ProteomicsDB; 72977; -. [Q8ND25-2]
DR Antibodypedia; 30290; 162 antibodies from 27 providers.
DR DNASU; 84937; -.
DR Ensembl; ENST00000320619.10; ENSP00000323362.6; ENSG00000186187.12. [Q8ND25-2]
DR Ensembl; ENST00000335325.9; ENSP00000335091.4; ENSG00000186187.12. [Q8ND25-1]
DR Ensembl; ENST00000567962.5; ENSP00000455601.1; ENSG00000186187.12. [Q8ND25-1]
DR GeneID; 84937; -.
DR KEGG; hsa:84937; -.
DR MANE-Select; ENST00000335325.9; ENSP00000335091.4; NM_032268.5; NP_115644.1.
DR UCSC; uc002fdk.4; human. [Q8ND25-1]
DR CTD; 84937; -.
DR DisGeNET; 84937; -.
DR GeneCards; ZNRF1; -.
DR HGNC; HGNC:18452; ZNRF1.
DR HPA; ENSG00000186187; Low tissue specificity.
DR MIM; 612060; gene.
DR neXtProt; NX_Q8ND25; -.
DR OpenTargets; ENSG00000186187; -.
DR PharmGKB; PA134938288; -.
DR VEuPathDB; HostDB:ENSG00000186187; -.
DR eggNOG; KOG0801; Eukaryota.
DR GeneTree; ENSGT00940000159278; -.
DR HOGENOM; CLU_062700_0_1_1; -.
DR InParanoid; Q8ND25; -.
DR OMA; YNVRTQR; -.
DR OrthoDB; 1256682at2759; -.
DR PhylomeDB; Q8ND25; -.
DR TreeFam; TF317681; -.
DR BRENDA; 2.3.2.27; 2681.
DR PathwayCommons; Q8ND25; -.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; Q8ND25; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 84937; 11 hits in 1117 CRISPR screens.
DR ChiTaRS; ZNRF1; human.
DR GeneWiki; ZNRF1; -.
DR GenomeRNAi; 84937; -.
DR Pharos; Q8ND25; Tbio.
DR PRO; PR:Q8ND25; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q8ND25; protein.
DR Bgee; ENSG00000186187; Expressed in lower esophagus mucosa and 185 other tissues.
DR ExpressionAtlas; Q8ND25; baseline and differential.
DR Genevisible; Q8ND25; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0005768; C:endosome; IDA:LIFEdb.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0030672; C:synaptic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; ISS:UniProtKB.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR Pfam; PF13639; zf-RING_2; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasmic vesicle; Endosome;
KW Lipoprotein; Lysosome; Membrane; Metal-binding; Myristate; Phosphoprotein;
KW Reference proteome; Synapse; Transferase; Ubl conjugation pathway; Zinc;
KW Zinc-finger.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000305"
FT CHAIN 2..227
FT /note="E3 ubiquitin-protein ligase ZNRF1"
FT /id="PRO_0000277799"
FT ZN_FING 184..225
FT /note="RING-type; atypical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 1..42
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2..10
FT /note="Required for endosomal and lysosomal localization
FT and myristoylation"
FT REGION 68..105
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 52
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 53
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 123
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000305|PubMed:14561866"
FT VAR_SEQ 173
FT /note="N -> NGRIQRSLRGAQPEKTWLSGRTLQEQPWRTECSWAPMAQMQSYPHCP
FT VENRE (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11230166"
FT /id="VSP_023088"
FT MUTAGEN 184
FT /note="C->A: Loss of E3 activity."
FT /evidence="ECO:0000269|PubMed:14561866"
FT TURN 146..148
FT /evidence="ECO:0007829|PDB:5YWR"
FT HELIX 154..156
FT /evidence="ECO:0007829|PDB:5YWR"
FT HELIX 157..164
FT /evidence="ECO:0007829|PDB:5YWR"
FT STRAND 173..176
FT /evidence="ECO:0007829|PDB:5YWR"
FT TURN 185..187
FT /evidence="ECO:0007829|PDB:5YWR"
FT STRAND 196..199
FT /evidence="ECO:0007829|PDB:5YWR"
FT STRAND 205..207
FT /evidence="ECO:0007829|PDB:5YWR"
FT HELIX 208..215
FT /evidence="ECO:0007829|PDB:5YWR"
SQ SEQUENCE 227 AA; 23783 MW; 41BCF1AAEDD0C52C CRC64;
MGGKQSTAAR SRGPFPGVST DDSAVPPPGG APHFGHYRTG GGAMGLRSRS VSSVAGMGMD
PSTAGGVPFG LYTPASRGTG DSERAPGGGG SASDSTYAHG NGYQETGGGH HRDGMLYLGS
RASLADALPL HIAPRWFSSH SGFKCPICSK SVASDEMEMH FIMCLSKPRL SYNDDVLTKD
AGECVICLEE LLQGDTIARL PCLCIYHKSC IDSWFEVNRS CPEHPAD
