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WWP1_MOUSE
ID   WWP1_MOUSE              Reviewed;         918 AA.
AC   Q8BZZ3; Q8BIV9; Q8VDP8;
DT   20-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT   20-JUN-2003, sequence version 2.
DT   03-AUG-2022, entry version 167.
DE   RecName: Full=NEDD4-like E3 ubiquitin-protein ligase WWP1;
DE            EC=2.3.2.26;
DE   AltName: Full=HECT-type E3 ubiquitin transferase WWP1;
DE   AltName: Full=WW domain-containing protein 1;
GN   Name=Wwp1;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Testis;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 639-918.
RC   STRAIN=FVB/N; TISSUE=Colon, and Mammary cancer;
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   [3]
RP   INTERACTION WITH KLF2.
RX   PubMed=11375995; DOI=10.1074/jbc.m103670200;
RA   Conkright M.D., Wani M.A., Lingrel J.B.;
RT   "Lung Krueppel-like factor contains an autoinhibitory domain that regulates
RT   its transcriptional activation by binding WWP1, an E3 ubiquitin ligase.";
RL   J. Biol. Chem. 276:29299-29306(2001).
RN   [4]
RP   FUNCTION IN UBIQUITINATION OF KLF2, AND MUTAGENESIS OF CYS-886.
RX   PubMed=15003522; DOI=10.1016/j.bbrc.2004.02.033;
RA   Zhang X., Srinivasan S.V., Lingrel J.B.;
RT   "WWP1-dependent ubiquitination and degradation of the lung Kruppel-like
RT   factor, KLF2.";
RL   Biochem. Biophys. Res. Commun. 316:139-148(2004).
RN   [5]
RP   FUNCTION IN UBIQUITINATION OF KLF5, INTERACTION WITH KLF5, SUBCELLULAR
RP   LOCATION, AND MUTAGENESIS OF CYS-886.
RX   PubMed=15735697; DOI=10.1038/sj.onc.1208497;
RA   Chen C., Sun X., Ran Q., Wilkinson K.D., Murphy T.J., Simons J.W.,
RA   Dong J.T.;
RT   "Ubiquitin-proteasome degradation of KLF5 transcription factor in cancer
RT   and untransformed epithelial cells.";
RL   Oncogene 24:3319-3327(2005).
RN   [6]
RP   INTERACTION WITH HIVEP3.
RX   PubMed=16728642; DOI=10.1126/science.1126313;
RA   Jones D.C., Wein M.N., Oukka M., Hofstaetter J.G., Glimcher M.J.,
RA   Glimcher L.H.;
RT   "Regulation of adult bone mass by the zinc finger adapter protein Schnurri-
RT   3.";
RL   Science 312:1223-1227(2006).
RN   [7]
RP   FUNCTION IN UBIQUITINATION OF TP63, AND INTERACTION WITH TP63.
RX   PubMed=18806757; DOI=10.1038/cdd.2008.134;
RA   Li Y., Zhou Z., Chen C.;
RT   "WW domain-containing E3 ubiquitin protein ligase 1 targets p63
RT   transcription factor for ubiquitin-mediated proteasomal degradation and
RT   regulates apoptosis.";
RL   Cell Death Differ. 15:1941-1951(2008).
RN   [8]
RP   FUNCTION IN UBIQUITINATION OF RNF11, INTERACTION WITH RNF11,
RP   UBIQUITINATION, AND MUTAGENESIS OF CYS-886.
RX   PubMed=18724389; DOI=10.1038/onc.2008.288;
RA   Chen C., Zhou Z., Liu R., Li Y., Azmi P.B., Seth A.K.;
RT   "The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2
RT   and EGFR through RING finger protein 11.";
RL   Oncogene 27:6845-6855(2008).
RN   [9]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA   Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA   Thibault P.;
RT   "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL   Immunity 30:143-154(2009).
RN   [10]
RP   FUNCTION IN UBIQUITINATION OF ERBB4, AND INTERACTION WITH ERBB4.
RX   PubMed=19561640; DOI=10.1038/onc.2009.162;
RA   Li Y., Zhou Z., Alimandi M., Chen C.;
RT   "WW domain containing E3 ubiquitin protein ligase 1 targets the full-length
RT   ErbB4 for ubiquitin-mediated degradation in breast cancer.";
RL   Oncogene 28:2948-2958(2009).
CC   -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an
CC       E2 ubiquitin-conjugating enzyme in the form of a thioester and then
CC       directly transfers the ubiquitin to targeted substrates. Ubiquitinates
CC       and promotes degradation of SMAD2 in response to TGF-beta signaling,
CC       which requires interaction with TGIF (By similarity). Ubiquitinates
CC       ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and
CC       promotes their proteasomal degradation. Ubiquitinates RNF11 without
CC       targeting it for degradation. Ubiquitinates and promotes degradation of
CC       TGFBR1; the ubiquitination is enhanced by SMAD7. Ubiquitinates SMAD6
CC       and SMAD7. {ECO:0000250, ECO:0000269|PubMed:15003522,
CC       ECO:0000269|PubMed:15735697, ECO:0000269|PubMed:18724389,
CC       ECO:0000269|PubMed:18806757, ECO:0000269|PubMed:19561640}.
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=2.3.2.26;
CC   -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC       {ECO:0000250}.
CC   -!- PATHWAY: Protein modification; protein ubiquitination.
CC   -!- SUBUNIT: Binds SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2, DRPLA and adenovirus
CC       type 2 PIII. Interacts with TGIF (By similarity). Binds KLF2 AND
CC       HIVEP3. Interacts with RNF11. Interacts with SPART. Interacts with
CC       NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein
CC       ligase (By similarity). Interacts with ERBB4 isoforms JM-B CYT-1 and
CC       JM-A CYT-1. Does not interact with ERB4 isoform JMA-A CYT-2. Interacts
CC       with SMAD1, SMAD2, SMAD3, SMAD5, SMAD6, SMAD7, TGFBR1 AND TGFBR2.
CC       Associates with the TGFBR1:TGFBR2 receptor complex in presence of
CC       SMAD7. Interacts with SKIL isoform 1. Interacts with TP63 isoform 1 and
CC       isoform 2. Interacts (via WW domains) with ARRDC1, ARRDC2 and ARRDC3
CC       (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q9H0M0,
CC       ECO:0000269|PubMed:11375995, ECO:0000269|PubMed:15735697,
CC       ECO:0000269|PubMed:16728642, ECO:0000269|PubMed:18724389,
CC       ECO:0000269|PubMed:18806757, ECO:0000269|PubMed:19561640}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15735697}. Cell
CC       membrane {ECO:0000269|PubMed:15735697}; Peripheral membrane protein
CC       {ECO:0000269|PubMed:15735697}. Nucleus {ECO:0000269|PubMed:15735697}.
CC   -!- DOMAIN: The WW domains mediate interaction with PPxY motif-containing
CC       proteins. {ECO:0000250|UniProtKB:Q9H0M0}.
CC   -!- PTM: Auto-ubiquitinated and ubiquitinated by RNF11. {ECO:0000250}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH21470.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC       Sequence=BAC38473.1; Type=Miscellaneous discrepancy; Note=Chimera. The second part of the clone maps to another chromosome.; Evidence={ECO:0000305};
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DR   EMBL; AK033138; BAC28168.1; -; mRNA.
DR   EMBL; AK082346; BAC38473.1; ALT_SEQ; mRNA.
DR   EMBL; BC021470; AAH21470.1; ALT_INIT; mRNA.
DR   EMBL; BC051405; AAH51405.1; -; mRNA.
DR   CCDS; CCDS38697.1; -.
DR   RefSeq; NP_001263221.1; NM_001276292.1.
DR   RefSeq; NP_796301.2; NM_177327.5.
DR   AlphaFoldDB; Q8BZZ3; -.
DR   SMR; Q8BZZ3; -.
DR   BioGRID; 223399; 8.
DR   IntAct; Q8BZZ3; 2.
DR   STRING; 10090.ENSMUSP00000103881; -.
DR   iPTMnet; Q8BZZ3; -.
DR   PhosphoSitePlus; Q8BZZ3; -.
DR   SwissPalm; Q8BZZ3; -.
DR   EPD; Q8BZZ3; -.
DR   jPOST; Q8BZZ3; -.
DR   MaxQB; Q8BZZ3; -.
DR   PaxDb; Q8BZZ3; -.
DR   PRIDE; Q8BZZ3; -.
DR   ProteomicsDB; 275222; -.
DR   Antibodypedia; 25465; 160 antibodies from 28 providers.
DR   DNASU; 107568; -.
DR   Ensembl; ENSMUST00000035982; ENSMUSP00000041627; ENSMUSG00000041058.
DR   Ensembl; ENSMUST00000108246; ENSMUSP00000103881; ENSMUSG00000041058.
DR   GeneID; 107568; -.
DR   KEGG; mmu:107568; -.
DR   UCSC; uc008scc.2; mouse.
DR   CTD; 11059; -.
DR   MGI; MGI:1861728; Wwp1.
DR   VEuPathDB; HostDB:ENSMUSG00000041058; -.
DR   eggNOG; KOG0940; Eukaryota.
DR   GeneTree; ENSGT00940000154635; -.
DR   HOGENOM; CLU_002173_0_1_1; -.
DR   InParanoid; Q8BZZ3; -.
DR   OMA; ANQGYHQ; -.
DR   OrthoDB; 167687at2759; -.
DR   PhylomeDB; Q8BZZ3; -.
DR   TreeFam; TF323658; -.
DR   Reactome; R-MMU-1253288; Downregulation of ERBB4 signaling.
DR   Reactome; R-MMU-2672351; Stimuli-sensing channels.
DR   Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR   UniPathway; UPA00143; -.
DR   BioGRID-ORCS; 107568; 3 hits in 73 CRISPR screens.
DR   ChiTaRS; Wwp1; mouse.
DR   PRO; PR:Q8BZZ3; -.
DR   Proteomes; UP000000589; Chromosome 4.
DR   RNAct; Q8BZZ3; protein.
DR   Bgee; ENSMUSG00000041058; Expressed in stroma of bone marrow and 241 other tissues.
DR   Genevisible; Q8BZZ3; MM.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI.
DR   GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR   GO; GO:0030324; P:lung development; TAS:UniProtKB.
DR   GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR   GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR   GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR   GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR   GO; GO:0030217; P:T cell differentiation; TAS:UniProtKB.
DR   CDD; cd00078; HECTc; 1.
DR   CDD; cd00201; WW; 4.
DR   Gene3D; 2.60.40.150; -; 1.
DR   InterPro; IPR000008; C2_dom.
DR   InterPro; IPR035892; C2_domain_sf.
DR   InterPro; IPR024928; E3_ub_ligase_SMURF1.
DR   InterPro; IPR000569; HECT_dom.
DR   InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR   InterPro; IPR001202; WW_dom.
DR   InterPro; IPR036020; WW_dom_sf.
DR   Pfam; PF00168; C2; 1.
DR   Pfam; PF00632; HECT; 1.
DR   Pfam; PF00397; WW; 4.
DR   PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
DR   SMART; SM00239; C2; 1.
DR   SMART; SM00119; HECTc; 1.
DR   SMART; SM00456; WW; 4.
DR   SUPFAM; SSF49562; SSF49562; 1.
DR   SUPFAM; SSF51045; SSF51045; 4.
DR   SUPFAM; SSF56204; SSF56204; 1.
DR   PROSITE; PS50004; C2; 1.
DR   PROSITE; PS50237; HECT; 1.
DR   PROSITE; PS01159; WW_DOMAIN_1; 4.
DR   PROSITE; PS50020; WW_DOMAIN_2; 4.
PE   1: Evidence at protein level;
KW   Cell membrane; Cytoplasm; Membrane; Nucleus; Reference proteome; Repeat;
KW   Transferase; Ubl conjugation; Ubl conjugation pathway.
FT   CHAIN           1..918
FT                   /note="NEDD4-like E3 ubiquitin-protein ligase WWP1"
FT                   /id="PRO_0000120337"
FT   DOMAIN          1..116
FT                   /note="C2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT   DOMAIN          345..378
FT                   /note="WW 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT   DOMAIN          377..410
FT                   /note="WW 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT   DOMAIN          452..485
FT                   /note="WW 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT   DOMAIN          492..525
FT                   /note="WW 4"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT   DOMAIN          584..918
FT                   /note="HECT"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT   REGION          150..182
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          209..360
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          345..525
FT                   /note="Interaction with ERBB4"
FT                   /evidence="ECO:0000269|PubMed:19561640"
FT   COMPBIAS        232..295
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        308..322
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        886
FT                   /note="Glycyl thioester intermediate"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT   SITE            886
FT                   /note="Required for ubiquitin-thioester formation"
FT   MUTAGEN         886
FT                   /note="C->S: Loss of catalytic activity. No effect on
FT                   RNF11-binding. No effect on KLF2 ubiquitination. Abolishes
FT                   ubiquitination of KLF5."
FT                   /evidence="ECO:0000269|PubMed:15003522,
FT                   ECO:0000269|PubMed:15735697, ECO:0000269|PubMed:18724389"
FT   CONFLICT        302
FT                   /note="V -> L (in Ref. 1; BAC28168)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   918 AA;  104694 MW;  01478A3C1CFFDAA9 CRC64;
     MATASPRSDT SDIHSGRLQL KVTVSSAKLK RKKNWFGTAI YTEVIVDGEV KKTAKSSSSS
     NPKWDEQLIV NVTPQTTLEF RVWSHHTLKA DALLGKATVD LKQVLLTHNR KLEKVKEQLK
     LSLENKNGIV QTGELTVVLD GLVIEQEPVT NRSSSPPIEI QQNGDALHEN GDPATRTTPR
     LPVEGTIGID NHVSTNTVVP NSCCSHVVNG ENTPSSPSQV AARPKNAPAP KPVTSAPTSD
     TVNGESSSVL ADNTSTMGTL LPSEDTTSTS NCTSTTTQEP PVQEPPASSE HSECIPSASA
     EVGPEARSLI DPDSDSRNNS VFDKVRQPEG CVEPLRPQSG NTNTEALPSG WEQRKDPHGR
     TYYVDHNTRT TTWERPQPLP PGWERRVDDR GRVYYVDHNT RTTTWQRPTM ESVRNFEQWQ
     SQRNQLQGAM QQFNQRYLYS ASMLAAENDP YGPLPPGWEK RVDSTDRVYF VNHNTKTTQW
     EDPRTQGLPN EEPLPEGWEI RYTREGVRYF VDHNTRTTTF KDPRNGKSSV TKGGPQIAYE
     RSFRWKLAHF RYLCQSNALP SHVKINVSRQ TLFEDSFQQI MALKPYDLRR RLYVIFRGEE
     GLDYGGLARE WFFLLSHEVL NPMYCLFEYA GKNNYCLQIN PASTINPDHL SYFCFIGRFI
     AMALFHGKFI DTGFSLPFYK RMLSKKLTIK DLESIDTEFY NSLIWIRDNN IEECGLEMYF
     SVDMEILGKV TSHDLKLGGS NILVTEENKD EYIGLMTEWR FSRGVQEQTK AFLDGFNEVV
     PLQWLQYFDE KELEVMLCGM QEVDLADWQR NTVYRHYTRN SKQIIWFWQF VKETDNEVRM
     RLLQFVTGTC RLPLGGFAEL MGSNGPQKFC IEKVGKDTWL PRSHTCFNRL DLPPYKSYEQ
     LKEKLLFAIE ETEGFGQE
 
 
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