ZNRF4_HUMAN
ID ZNRF4_HUMAN Reviewed; 429 AA.
AC Q8WWF5; A8K886; O75866;
DT 20-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 20-FEB-2007, sequence version 3.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=E3 ubiquitin-protein ligase ZNRF4 {ECO:0000305};
DE EC=2.3.2.27 {ECO:0000269|PubMed:28656966, ECO:0000305|PubMed:21205830};
DE AltName: Full=Nixin {ECO:0000303|PubMed:21205830};
DE AltName: Full=RING finger protein 204 {ECO:0000305};
DE AltName: Full=RING-type E3 ubiquitin transferase ZNRF4;
DE AltName: Full=Zinc/RING finger protein 4 {ECO:0000305};
DE Flags: Precursor;
GN Name=ZNRF4 {ECO:0000312|HGNC:HGNC:17726};
GN Synonyms=RNF204 {ECO:0000312|HGNC:HGNC:17726};
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 [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS SER-37 AND GLN-78 AND
RP HIS-163.
RC TISSUE=Testis;
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 [5]
RP FUNCTION, PATHWAY, INTERACTION WITH CANX, SUBCELLULAR LOCATION, TOPOLOGY,
RP DOMAIN, GLYCOSYLATION AT ASN-107; ASN-152 AND ASN-229, AND MUTAGENESIS OF
RP ASN-107; ASN-152; ASN-229 AND 329-HIS--HIS-332.
RX PubMed=21205830; DOI=10.1074/jbc.m110.197459;
RA Neutzner A., Neutzner M., Benischke A.S., Ryu S.W., Frank S., Youle R.J.,
RA Karbowski M.;
RT "A systematic search for endoplasmic reticulum (ER) membrane-associated
RT RING finger proteins identifies Nixin/ZNRF4 as a regulator of calnexin
RT stability and ER homeostasis.";
RL J. Biol. Chem. 286:8633-8643(2011).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=24387786; DOI=10.1042/bj20131067;
RA van Dijk J.R., Yamazaki Y., Palmer R.H.;
RT "Tumour-associated mutations of PA-TM-RING ubiquitin ligases RNF167/RNF13
RT identify the PA domain as a determinant for endosomal localization.";
RL Biochem. J. 459:27-36(2014).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF 329-HIS--HIS-332.
RX PubMed=28656966; DOI=10.1038/ncomms15865;
RA Bist P., Cheong W.S., Ng A., Dikshit N., Kim B.H., Pulloor N.K.,
RA Khameneh H.J., Hedl M., Shenoy A.R., Balamuralidhar V., Malik N.B.A.,
RA Hong M., Neutzner A., Chin K.C., Kobayashi K.S., Bertoletti A.,
RA Mortellaro A., Abraham C., MacMicking J.D., Xavier R.J., Sukumaran B.;
RT "E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces
RT tolerance to MDP.";
RL Nat. Commun. 8:15865-15865(2017).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator
CC of NOD2 signaling by mediating ubiquitination and degradation of RIPK2
CC (PubMed:28656966). Also catalyzes ubiquitination and proteasomal
CC degradation of CANX within the endoplasmic reticulum (PubMed:21205830).
CC Could have a role in spermatogenesis (By similarity).
CC {ECO:0000250|UniProtKB:Q9DAH2, ECO:0000269|PubMed:21205830,
CC ECO:0000269|PubMed:28656966}.
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; Evidence={ECO:0000269|PubMed:28656966,
CC ECO:0000305|PubMed:21205830};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:21205830, ECO:0000269|PubMed:28656966}.
CC -!- SUBUNIT: Interacts with CANX. {ECO:0000269|PubMed:21205830}.
CC -!- INTERACTION:
CC Q8WWF5; P21589: NT5E; NbExp=3; IntAct=EBI-2129267, EBI-6393623;
CC Q8WWF5; Q8N7U7-2: TPRX1; NbExp=3; IntAct=EBI-2129267, EBI-14115717;
CC Q8WWF5; O00526: UPK2; NbExp=3; IntAct=EBI-2129267, EBI-10179682;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:21205830, ECO:0000269|PubMed:24387786,
CC ECO:0000269|PubMed:28656966}; Single-pass type I membrane protein
CC {ECO:0000255}.
CC -!- DOMAIN: The RING-type zinc finger is involved in CANX ubiquitination
CC and degradation, but is not required for interaction with CANX.
CC {ECO:0000269|PubMed:21205830}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC62428.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK292251; BAF84940.1; -; mRNA.
DR EMBL; AC005764; AAC62428.1; ALT_INIT; Genomic_DNA.
DR EMBL; CH471139; EAW69169.1; -; Genomic_DNA.
DR EMBL; BC017592; AAH17592.2; -; mRNA.
DR CCDS; CCDS42475.1; -.
DR RefSeq; NP_859061.3; NM_181710.3.
DR AlphaFoldDB; Q8WWF5; -.
DR SMR; Q8WWF5; -.
DR BioGRID; 127116; 169.
DR IntAct; Q8WWF5; 82.
DR STRING; 9606.ENSP00000222033; -.
DR GlyGen; Q8WWF5; 3 sites.
DR iPTMnet; Q8WWF5; -.
DR PhosphoSitePlus; Q8WWF5; -.
DR BioMuta; ZNRF4; -.
DR DMDM; 126253848; -.
DR MassIVE; Q8WWF5; -.
DR MaxQB; Q8WWF5; -.
DR PaxDb; Q8WWF5; -.
DR PeptideAtlas; Q8WWF5; -.
DR PRIDE; Q8WWF5; -.
DR ProteomicsDB; 74881; -.
DR Antibodypedia; 2299; 113 antibodies from 19 providers.
DR DNASU; 148066; -.
DR Ensembl; ENST00000222033.6; ENSP00000222033.4; ENSG00000105428.6.
DR GeneID; 148066; -.
DR KEGG; hsa:148066; -.
DR MANE-Select; ENST00000222033.6; ENSP00000222033.4; NM_181710.4; NP_859061.3.
DR UCSC; uc002mca.5; human.
DR CTD; 148066; -.
DR DisGeNET; 148066; -.
DR GeneCards; ZNRF4; -.
DR HGNC; HGNC:17726; ZNRF4.
DR HPA; ENSG00000105428; Tissue enriched (testis).
DR MIM; 612063; gene.
DR neXtProt; NX_Q8WWF5; -.
DR OpenTargets; ENSG00000105428; -.
DR PharmGKB; PA134943871; -.
DR VEuPathDB; HostDB:ENSG00000105428; -.
DR eggNOG; KOG4628; Eukaryota.
DR GeneTree; ENSGT00940000163061; -.
DR HOGENOM; CLU_035275_1_0_1; -.
DR InParanoid; Q8WWF5; -.
DR OMA; CDKSAHV; -.
DR OrthoDB; 1487241at2759; -.
DR PhylomeDB; Q8WWF5; -.
DR TreeFam; TF317486; -.
DR PathwayCommons; Q8WWF5; -.
DR SignaLink; Q8WWF5; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 148066; 7 hits in 1104 CRISPR screens.
DR GenomeRNAi; 148066; -.
DR Pharos; Q8WWF5; Tbio.
DR PRO; PR:Q8WWF5; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q8WWF5; protein.
DR Bgee; ENSG00000105428; Expressed in right testis and 43 other tissues.
DR Genevisible; Q8WWF5; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR CDD; cd02123; PA_C_RZF_like; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR003137; PA_domain.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR044744; ZNRF4/RNF13/RNF167_PA.
DR Pfam; PF02225; PA; 1.
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 Endoplasmic reticulum; Glycoprotein; Membrane; Metal-binding;
KW Reference proteome; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Zinc; Zinc-finger.
FT SIGNAL 1..27
FT /evidence="ECO:0000255"
FT CHAIN 28..429
FT /note="E3 ubiquitin-protein ligase ZNRF4"
FT /id="PRO_0000277861"
FT TOPO_DOM 28..250
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:21205830"
FT TRANSMEM 251..271
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 272..429
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:21205830"
FT DOMAIN 151..223
FT /note="PA"
FT /evidence="ECO:0000255"
FT ZN_FING 309..352
FT /note="RING-type; atypical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 30..67
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 107
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:21205830"
FT CARBOHYD 152
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:21205830"
FT CARBOHYD 229
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:21205830"
FT VARIANT 37
FT /note="P -> S (in dbSNP:rs2240743)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_030611"
FT VARIANT 78
FT /note="R -> Q (in dbSNP:rs2240744)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_030612"
FT VARIANT 100
FT /note="V -> I (in dbSNP:rs2240745)"
FT /id="VAR_030613"
FT VARIANT 157
FT /note="A -> S (in dbSNP:rs8103406)"
FT /id="VAR_030614"
FT VARIANT 159
FT /note="V -> A (in dbSNP:rs8107825)"
FT /id="VAR_030615"
FT VARIANT 163
FT /note="R -> C (in dbSNP:rs8104246)"
FT /id="VAR_030616"
FT VARIANT 163
FT /note="R -> H (in dbSNP:rs17304380)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_030617"
FT VARIANT 192
FT /note="D -> N (in dbSNP:rs16992985)"
FT /id="VAR_030618"
FT MUTAGEN 107
FT /note="N->S: Abolishes glycosylation; when associated with
FT S-152 and S-229."
FT /evidence="ECO:0000269|PubMed:21205830"
FT MUTAGEN 152
FT /note="N->S: Abolishes glycosylation; when associated with
FT S-107 and S-229."
FT /evidence="ECO:0000269|PubMed:21205830"
FT MUTAGEN 229
FT /note="N->S: Abolishes glycosylation; when associated with
FT S-107 and S-152."
FT /evidence="ECO:0000269|PubMed:21205830"
FT MUTAGEN 329..332
FT /note="HTYH->WTYW: Abolished E3 ubiquitin-protein ligase
FT activity."
FT /evidence="ECO:0000269|PubMed:21205830,
FT ECO:0000269|PubMed:28656966"
FT CONFLICT 157..159
FT /note="AIV -> SIA (in Ref. 4; AAH17592)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 429 AA; 46958 MW; 9924ED37BC00644D CRC64;
MPLCRPEHLM PRASRVPVAA SLPLSHAVIP TQLPSRPGHR PPGRPRRCPK ASCLPPPVGP
SSTQTAKRVT MGWPRPGRAL VAVKALLVLS LLQVPAQAVV RAVLEDNSSS VDFADLPALF
GVPLAPEGIR GYLMEVKPAN ACHPIEAPRL GNRSLGAIVL IRRYDCTFDL KVLNAQRAGF
EAAIVHNVHS DDLVSMTHVY EDLRGQIAIP SVFVSEAASQ DLRVILGCNK SAHALLLPDD
PPCHDLGCHP VLTVSWVLGC TLALVVSAFF VLNHLWLWAQ ACCSHRRPVK TSTCQKAQVR
TFTWHNDLCA ICLDEYEEGD QLKILPCSHT YHCKCIDPWF SQAPRRSCPV CKQSVAATED
SFDSTTYSFR DEDPSLPGHR PPIWAIQVQL RSRRLELLGR ASPHCHCSTT SLEAEYTTVS
SAPPEAPGQ
