WWP2_HUMAN
ID WWP2_HUMAN Reviewed; 870 AA.
AC O00308; A6NEP1; B2R706; B4DTL5; F5H213; H3BRF3; I3RSG8; Q6ZTQ5; Q96CZ2;
AC Q9BWN6;
DT 20-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 20-JUN-2003, sequence version 2.
DT 03-AUG-2022, entry version 206.
DE RecName: Full=NEDD4-like E3 ubiquitin-protein ligase WWP2;
DE EC=2.3.2.26 {ECO:0000269|PubMed:19274063, ECO:0000269|PubMed:19651900};
DE AltName: Full=Atrophin-1-interacting protein 2;
DE Short=AIP2;
DE AltName: Full=HECT-type E3 ubiquitin transferase WWP2;
DE AltName: Full=WW domain-containing protein 2;
GN Name=WWP2;
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 INTERACTION WITH WBP1; WBP2;
RP SCNN1A; SCNN1B AND SCNN1G.
RC TISSUE=Bone marrow, and Brain;
RX PubMed=9169421; DOI=10.1074/jbc.272.23.14611;
RA Pirozzi G., McConnell S.J., Uveges A.J., Carter J.M., Sparks A.B.,
RA Kay B.K., Fowlkes D.M.;
RT "Identification of novel human WW domain-containing proteins by cloning of
RT ligand targets.";
RL J. Biol. Chem. 272:14611-14616(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Jiang G.Y., Yang J.H., Liu S.F.;
RT "Bioinformatic analysis of E3 ligase WWP2 in 14 different vertebrates.";
RL Submitted (SEP-2011) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Placenta, Testis, and Trachea;
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 [4]
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 [5]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
RC TISSUE=Brain, Ovary, and Placenta;
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 [7]
RP INTERACTION WITH ATN1, AND TISSUE SPECIFICITY.
RX PubMed=9647693; DOI=10.1006/mcne.1998.0677;
RA Wood J.D., Yuan J., Margolis R.L., Colomer V., Duan K., Kushi J.,
RA Kaminsky Z., Kleiderlein J.J. Jr., Sharp A.H., Ross C.A.;
RT "Atrophin-1, the DRPLA gene product, interacts with two families of WW
RT domain-containing proteins.";
RL Mol. Cell. Neurosci. 11:149-160(1998).
RN [8]
RP INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G.
RX PubMed=12167593; DOI=10.1152/ajprenal.00080.2002;
RA McDonald F.J., Western A.H., McNeil J.D., Thomas B.C., Olson D.R.,
RA Snyder P.M.;
RT "Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial
RT Na(+) channel.";
RL Am. J. Physiol. 283:F431-F436(2002).
RN [9]
RP INTERACTION WITH ADENOVIRUS TYPE 2 PIII (MICROBIAL INFECTION).
RX PubMed=12450395; DOI=10.1021/bi020125b;
RA Galinier R., Gout E., Lortat-Jacob H., Wood J., Chroboczek J.;
RT "Adenovirus protein involved in virus internalization recruits ubiquitin-
RT protein ligases.";
RL Biochemistry 41:14299-14305(2002).
RN [10]
RP INTERACTION WITH NDFIP1.
RX PubMed=11748237; DOI=10.1074/jbc.m110443200;
RA Harvey K.F., Shearwin-Whyatt L.M., Fotia A., Parton R.G., Kumar S.;
RT "N4WBP5, a potential target for ubiquitination by the Nedd4 family of
RT proteins, is a novel Golgi-associated protein.";
RL J. Biol. Chem. 277:9307-9317(2002).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-211, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP AUTOINHIBITION BY C2 DOMAIN.
RX PubMed=17719543; DOI=10.1016/j.cell.2007.06.050;
RA Wiesner S., Ogunjimi A.A., Wang H.R., Rotin D., Sicheri F., Wrana J.L.,
RA Forman-Kay J.D.;
RT "Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2
RT domain.";
RL Cell 130:651-662(2007).
RN [13]
RP FUNCTION IN UBIQUITINATION OF POU5F1, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, DEVELOPMENTAL STAGE, INTERACTION WITH POU5F1, AND MUTAGENESIS
RP OF CYS-838.
RX PubMed=19274063; DOI=10.1038/cr.2009.31;
RA Xu H., Wang W., Li C., Yu H., Yang A., Wang B., Jin Y.;
RT "WWP2 promotes degradation of transcription factor OCT4 in human embryonic
RT stem cells.";
RL Cell Res. 19:561-573(2009).
RN [14]
RP ACTIVATION BY NDFIP1 AND NDFIP2, AND AUTOUBIQUITINATION.
RX PubMed=19343052; DOI=10.1038/embor.2009.30;
RA Mund T., Pelham H.R.;
RT "Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP
RT proteins.";
RL EMBO Rep. 10:501-507(2009).
RN [15]
RP FUNCTION IN UBIQUITINATION OF EGR2, AND INTERACTION WITH EGR2.
RX PubMed=19651900; DOI=10.1128/mcb.00407-09;
RA Chen A., Gao B., Zhang J., McEwen T., Ye S.Q., Zhang D., Fang D.;
RT "The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell
RT death by catalyzing EGR2 ubiquitination.";
RL Mol. Cell. Biol. 29:5348-5356(2009).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH ERBB4, AND
RP SUBCELLULAR LOCATION.
RX PubMed=20858735; DOI=10.1158/1541-7786.mcr-10-0042;
RA Gilmore-Hebert M., Ramabhadran R., Stern D.F.;
RT "Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage
RT response pathways.";
RL Mol. Cancer Res. 8:1388-1398(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP UBIQUITINATION, AND MUTAGENESIS OF LYS-498 AND HIS-500.
RX PubMed=21572392; DOI=10.1038/emboj.2011.155;
RA Cui Y., He S., Xing C., Lu K., Wang J., Xing G., Meng A., Jia S., He F.,
RA Zhang L.;
RT "SCF(FBXL15) regulates BMP signalling by directing the degradation of HECT-
RT type ubiquitin ligase Smurf1.";
RL EMBO J. 30:2675-2689(2011).
RN [19]
RP INTERACTION WITH ARRDC1; ARRDC2 AND ARRDC3, AND DOMAIN.
RX PubMed=21191027; DOI=10.1128/jvi.02045-10;
RA Rauch S., Martin-Serrano J.;
RT "Multiple interactions between the ESCRT machinery and arrestin-related
RT proteins: implications for PPXY-dependent budding.";
RL J. Virol. 85:3546-3556(2011).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-211, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [21]
RP INTERACTION WITH ARRDC4.
RX PubMed=23236378; DOI=10.1371/journal.pone.0050557;
RA Shea F.F., Rowell J.L., Li Y., Chang T.H., Alvarez C.E.;
RT "Mammalian alpha arrestins link activated seven transmembrane receptors to
RT Nedd4 family e3 ubiquitin ligases and interact with beta arrestins.";
RL PLoS ONE 7:E50557-E50557(2012).
RN [22]
RP INTERACTION WITH ARRDC1, AND DOMAIN.
RX PubMed=22315426; DOI=10.1073/pnas.1200448109;
RA Nabhan J.F., Hu R., Oh R.S., Cohen S.N., Lu Q.;
RT "Formation and release of arrestin domain-containing protein 1-mediated
RT microvesicles (ARMMs) at plasma membrane by recruitment of TSG101
RT protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:4146-4151(2012).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-211, 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).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.51 ANGSTROMS) OF 492-865.
RX PubMed=26457515; DOI=10.1107/s2053230x1501554x;
RA Gong W., Zhang X., Zhang W., Li J., Li Z.;
RT "Structure of the HECT domain of human WWP2.";
RL Acta Crystallogr. F 71:1251-1257(2015).
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.
CC Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it
CC to proteasomal degradation; in embryonic stem cells (ESCs) the
CC ubiquitination is proposed to regulate POU5F1 protein level.
CC Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-
CC cells the ubiquitination inhibits activation-induced cell death.
CC Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of
CC NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal
CC degradation. {ECO:0000269|PubMed:19274063,
CC ECO:0000269|PubMed:19651900}.
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; Evidence={ECO:0000269|PubMed:19274063,
CC ECO:0000269|PubMed:19651900};
CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC {ECO:0000269|PubMed:19343052}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:19274063, ECO:0000269|PubMed:19651900}.
CC -!- SUBUNIT: Interacts with POU5F1, RBP1, EGR2 and SLC11A2 (By similarity).
CC Interacts with SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2 and ATN1. Interacts
CC with ERBB4, NDFIP1 AND NDFIP2. Interacts with ARRDC4 (PubMed:23236378).
CC Interacts (via WW domains) with ARRDC1 (via PPxY motifs); ubiquitinates
CC ARRDC1 (PubMed:22315426, PubMed:21191027). Interacts (via WW domains)
CC with ARRDC2 and ARRDC3 (PubMed:21191027).
CC {ECO:0000250|UniProtKB:Q9DBH0, ECO:0000269|PubMed:11748237,
CC ECO:0000269|PubMed:12167593, ECO:0000269|PubMed:19274063,
CC ECO:0000269|PubMed:19651900, ECO:0000269|PubMed:20858735,
CC ECO:0000269|PubMed:21191027, ECO:0000269|PubMed:22315426,
CC ECO:0000269|PubMed:23236378, ECO:0000269|PubMed:9169421,
CC ECO:0000269|PubMed:9647693}.
CC -!- SUBUNIT: (Microbial infection) Interacts with adenovirus type 2 PIII.
CC {ECO:0000269|PubMed:12450395}.
CC -!- INTERACTION:
CC O00308; P78563: ADARB1; NbExp=5; IntAct=EBI-743923, EBI-2967304;
CC O00308; Q8N8A2: ANKRD44; NbExp=5; IntAct=EBI-743923, EBI-1245329;
CC O00308; Q8N5I2: ARRDC1; NbExp=5; IntAct=EBI-743923, EBI-2339564;
CC O00308; Q96B67: ARRDC3; NbExp=5; IntAct=EBI-743923, EBI-2875665;
CC O00308; Q86V38: ATN1; NbExp=3; IntAct=EBI-743923, EBI-11954292;
CC O00308; P48643: CCT5; NbExp=6; IntAct=EBI-743923, EBI-355710;
CC O00308; Q9NWW5: CLN6; NbExp=3; IntAct=EBI-743923, EBI-6165897;
CC O00308; P07339: CTSD; NbExp=3; IntAct=EBI-743923, EBI-2115097;
CC O00308; Q14203-5: DCTN1; NbExp=3; IntAct=EBI-743923, EBI-25840379;
CC O00308; G5E9A7: DMWD; NbExp=3; IntAct=EBI-743923, EBI-10976677;
CC O00308; P50570-2: DNM2; NbExp=3; IntAct=EBI-743923, EBI-10968534;
CC O00308; Q14204: DYNC1H1; NbExp=3; IntAct=EBI-743923, EBI-356015;
CC O00308; Q8N7B9-2: EFCAB3; NbExp=3; IntAct=EBI-743923, EBI-11958551;
CC O00308; Q15884: FAM189A2; NbExp=4; IntAct=EBI-743923, EBI-8636612;
CC O00308; Q7L5A3: FAM214B; NbExp=3; IntAct=EBI-743923, EBI-745689;
CC O00308; Q96D16: FBXL18; NbExp=3; IntAct=EBI-743923, EBI-744419;
CC O00308; Q8TAE8: GADD45GIP1; NbExp=3; IntAct=EBI-743923, EBI-372506;
CC O00308; Q8NHY3: GAS2L2; NbExp=3; IntAct=EBI-743923, EBI-7960826;
CC O00308; Q86UU5: GGN; NbExp=3; IntAct=EBI-743923, EBI-10259069;
CC O00308; P07686: HEXB; NbExp=3; IntAct=EBI-743923, EBI-7133736;
CC O00308; Q9BUJ2: HNRNPUL1; NbExp=9; IntAct=EBI-743923, EBI-1018153;
CC O00308; O43464: HTRA2; NbExp=3; IntAct=EBI-743923, EBI-517086;
CC O00308; P42858: HTT; NbExp=9; IntAct=EBI-743923, EBI-466029;
CC O00308; Q8IZ03: IFIT2; NbExp=3; IntAct=EBI-743923, EBI-746217;
CC O00308; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-743923, EBI-1055254;
CC O00308; Q92876: KLK6; NbExp=3; IntAct=EBI-743923, EBI-2432309;
CC O00308; Q3B8N2: LGALS9B; NbExp=5; IntAct=EBI-743923, EBI-10240775;
CC O00308; Q99732: LITAF; NbExp=3; IntAct=EBI-743923, EBI-725647;
CC O00308; Q71SY5: MED25; NbExp=3; IntAct=EBI-743923, EBI-394558;
CC O00308; Q9HBE1-4: PATZ1; NbExp=3; IntAct=EBI-743923, EBI-11022007;
CC O00308; Q9NR12: PDLIM7; NbExp=6; IntAct=EBI-743923, EBI-350517;
CC O00308; O43933: PEX1; NbExp=3; IntAct=EBI-743923, EBI-988601;
CC O00308; Q01860: POU5F1; NbExp=4; IntAct=EBI-743923, EBI-475687;
CC O00308; P54646: PRKAA2; NbExp=3; IntAct=EBI-743923, EBI-1383852;
CC O00308; O60260-5: PRKN; NbExp=3; IntAct=EBI-743923, EBI-21251460;
CC O00308; P60891: PRPS1; NbExp=3; IntAct=EBI-743923, EBI-749195;
CC O00308; Q9Y272: RASD1; NbExp=3; IntAct=EBI-743923, EBI-740818;
CC O00308; Q9Y3C5: RNF11; NbExp=7; IntAct=EBI-743923, EBI-396669;
CC O00308; Q9BVN2: RUSC1; NbExp=3; IntAct=EBI-743923, EBI-6257312;
CC O00308; Q15599: SLC9A3R2; NbExp=3; IntAct=EBI-743923, EBI-1149760;
CC O00308; Q15796: SMAD2; NbExp=4; IntAct=EBI-743923, EBI-1040141;
CC O00308; P84022: SMAD3; NbExp=7; IntAct=EBI-743923, EBI-347161;
CC O00308; O15105: SMAD7; NbExp=5; IntAct=EBI-743923, EBI-3861591;
CC O00308; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-743923, EBI-358489;
CC O00308; Q99954: SMR3A; NbExp=3; IntAct=EBI-743923, EBI-12067698;
CC O00308; P37840: SNCA; NbExp=3; IntAct=EBI-743923, EBI-985879;
CC O00308; P14678-2: SNRPB; NbExp=3; IntAct=EBI-743923, EBI-372475;
CC O00308; P09234: SNRPC; NbExp=3; IntAct=EBI-743923, EBI-766589;
CC O00308; Q5TAL4: SNRPC; NbExp=3; IntAct=EBI-743923, EBI-10246938;
CC O00308; Q13148: TARDBP; NbExp=3; IntAct=EBI-743923, EBI-372899;
CC O00308; O14773: TPP1; NbExp=3; IntAct=EBI-743923, EBI-2800203;
CC O00308; Q9BUZ4: TRAF4; NbExp=7; IntAct=EBI-743923, EBI-3650647;
CC O00308; P22314: UBA1; NbExp=3; IntAct=EBI-743923, EBI-709688;
CC O00308; Q96LR5: UBE2E2; NbExp=3; IntAct=EBI-743923, EBI-2129763;
CC O00308; Q969T4: UBE2E3; NbExp=3; IntAct=EBI-743923, EBI-348496;
CC O00308; Q9HAC8: UBTD1; NbExp=3; IntAct=EBI-743923, EBI-745871;
CC O00308; A5D8V6: VPS37C; NbExp=6; IntAct=EBI-743923, EBI-2559305;
CC O00308; P61964: WDR5; NbExp=3; IntAct=EBI-743923, EBI-540834;
CC O00308; O76024: WFS1; NbExp=6; IntAct=EBI-743923, EBI-720609;
CC O00308; O43516: WIPF1; NbExp=4; IntAct=EBI-743923, EBI-346356;
CC O00308; A0A0S2Z5X4: ZNF688; NbExp=3; IntAct=EBI-743923, EBI-16429014;
CC O00308; Q8WU02; NbExp=3; IntAct=EBI-743923, EBI-747182;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:19274063,
CC ECO:0000269|PubMed:20858735}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=O00308-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O00308-2; Sequence=VSP_044706;
CC Name=3;
CC IsoId=O00308-3; Sequence=VSP_046461;
CC Name=4;
CC IsoId=O00308-4; Sequence=VSP_054711;
CC -!- TISSUE SPECIFICITY: Detected in heart, throughout the brain, placenta,
CC lung, liver, muscle, kidney and pancreas. Also detected in spleen and
CC peripheral blood leukocytes. {ECO:0000269|PubMed:19274063,
CC ECO:0000269|PubMed:9647693}.
CC -!- DEVELOPMENTAL STAGE: Highly expressed in undifferentiated embryonic
CC stem cells and expression is reduced after embryoid body (EB)
CC formation. Not detectable at day 13 of EB formation; low levels are
CC again detected at day 18 of EB formation.
CC {ECO:0000269|PubMed:19274063}.
CC -!- DOMAIN: The C2 domain is involved in autoinhibition of the catalytic
CC activity by interacting with the HECT domain. {ECO:0000250}.
CC -!- DOMAIN: The WW domains mediate interaction with PPxY motif-containing
CC proteins. {ECO:0000269|PubMed:21191027, ECO:0000269|PubMed:22315426}.
CC -!- PTM: Autoubiquitinated. Ubiquitinated by the SCF(FBXL15) complex,
CC leading to its degradation by the proteasome.
CC {ECO:0000269|PubMed:19343052, ECO:0000269|PubMed:21572392}.
CC -!- MISCELLANEOUS: A cysteine residue is required for ubiquitin-thioester
CC formation.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC86528.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; U96114; AAC51325.1; -; mRNA.
DR EMBL; JN712744; AFK29253.1; -; mRNA.
DR EMBL; AK126332; BAC86528.1; ALT_FRAME; mRNA.
DR EMBL; AK300266; BAG62027.1; -; mRNA.
DR EMBL; AK312792; BAG35653.1; -; mRNA.
DR EMBL; AC026468; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC092115; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471092; EAW83287.1; -; Genomic_DNA.
DR EMBL; BC000108; AAH00108.1; -; mRNA.
DR EMBL; BC013645; AAH13645.1; -; mRNA.
DR EMBL; BC064531; AAH64531.1; -; mRNA.
DR CCDS; CCDS10885.1; -. [O00308-1]
DR CCDS; CCDS58475.1; -. [O00308-4]
DR CCDS; CCDS58476.1; -. [O00308-2]
DR CCDS; CCDS58477.1; -. [O00308-3]
DR RefSeq; NP_001257382.1; NM_001270453.1. [O00308-2]
DR RefSeq; NP_001257383.1; NM_001270454.1. [O00308-1]
DR RefSeq; NP_001257384.1; NM_001270455.1. [O00308-4]
DR RefSeq; NP_008945.2; NM_007014.4. [O00308-1]
DR RefSeq; NP_955456.1; NM_199424.2. [O00308-3]
DR RefSeq; XP_011521125.1; XM_011522823.2. [O00308-1]
DR RefSeq; XP_011521127.1; XM_011522825.1. [O00308-1]
DR RefSeq; XP_011521128.1; XM_011522826.2. [O00308-2]
DR RefSeq; XP_016878368.1; XM_017022879.1. [O00308-1]
DR RefSeq; XP_016878369.1; XM_017022880.1. [O00308-1]
DR RefSeq; XP_016878370.1; XM_017022881.1. [O00308-1]
DR PDB; 4Y07; X-ray; 2.51 A; A=492-865.
DR PDB; 5TJ7; X-ray; 2.60 A; A/B/C/D=334-865.
DR PDB; 5TJ8; X-ray; 2.30 A; A=334-865.
DR PDB; 5TJQ; X-ray; 2.75 A; A=334-865.
DR PDB; 6J1Z; X-ray; 2.70 A; A=330-406, A=480-870.
DR PDB; 6RSS; NMR; -; A=438-480.
DR PDBsum; 4Y07; -.
DR PDBsum; 5TJ7; -.
DR PDBsum; 5TJ8; -.
DR PDBsum; 5TJQ; -.
DR PDBsum; 6J1Z; -.
DR PDBsum; 6RSS; -.
DR AlphaFoldDB; O00308; -.
DR SMR; O00308; -.
DR BioGRID; 116244; 810.
DR IntAct; O00308; 118.
DR MINT; O00308; -.
DR STRING; 9606.ENSP00000352069; -.
DR MoonDB; O00308; Predicted.
DR GlyGen; O00308; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O00308; -.
DR PhosphoSitePlus; O00308; -.
DR BioMuta; WWP2; -.
DR EPD; O00308; -.
DR jPOST; O00308; -.
DR MassIVE; O00308; -.
DR MaxQB; O00308; -.
DR PaxDb; O00308; -.
DR PeptideAtlas; O00308; -.
DR PRIDE; O00308; -.
DR ProteomicsDB; 25823; -.
DR ProteomicsDB; 42051; -.
DR ProteomicsDB; 47835; -. [O00308-1]
DR Antibodypedia; 29892; 214 antibodies from 25 providers.
DR DNASU; 11060; -.
DR Ensembl; ENST00000356003.6; ENSP00000348283.3; ENSG00000198373.13. [O00308-2]
DR Ensembl; ENST00000359154.7; ENSP00000352069.2; ENSG00000198373.13. [O00308-1]
DR Ensembl; ENST00000568684.1; ENSP00000456216.1; ENSG00000198373.13. [O00308-3]
DR Ensembl; ENST00000569174.5; ENSP00000455311.1; ENSG00000198373.13. [O00308-4]
DR GeneID; 11060; -.
DR KEGG; hsa:11060; -.
DR MANE-Select; ENST00000359154.7; ENSP00000352069.2; NM_001270454.2; NP_001257383.1.
DR UCSC; uc002exv.3; human. [O00308-1]
DR CTD; 11060; -.
DR DisGeNET; 11060; -.
DR GeneCards; WWP2; -.
DR HGNC; HGNC:16804; WWP2.
DR HPA; ENSG00000198373; Low tissue specificity.
DR MalaCards; WWP2; -.
DR MIM; 602308; gene.
DR neXtProt; NX_O00308; -.
DR OpenTargets; ENSG00000198373; -.
DR PharmGKB; PA134946925; -.
DR VEuPathDB; HostDB:ENSG00000198373; -.
DR eggNOG; KOG0940; Eukaryota.
DR GeneTree; ENSGT00940000160726; -.
DR HOGENOM; CLU_828900_0_0_1; -.
DR InParanoid; O00308; -.
DR OMA; FNAFITG; -.
DR PhylomeDB; O00308; -.
DR TreeFam; TF323658; -.
DR BRENDA; 2.3.2.26; 2681.
DR PathwayCommons; O00308; -.
DR Reactome; R-HSA-8948751; Regulation of PTEN stability and activity.
DR Reactome; R-HSA-9013406; RHOQ GTPase cycle.
DR Reactome; R-HSA-9013409; RHOJ GTPase cycle.
DR Reactome; R-HSA-9013420; RHOU GTPase cycle.
DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR SignaLink; O00308; -.
DR SIGNOR; O00308; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 11060; 13 hits in 1124 CRISPR screens.
DR ChiTaRS; WWP2; human.
DR GeneWiki; WWP2; -.
DR GenomeRNAi; 11060; -.
DR Pharos; O00308; Tbio.
DR PRO; PR:O00308; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; O00308; protein.
DR Bgee; ENSG00000198373; Expressed in tibia and 192 other tissues.
DR ExpressionAtlas; O00308; baseline and differential.
DR Genevisible; O00308; HS.
DR GO; GO:0005737; C:cytoplasm; ISS:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; TAS:ProtInc.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:BHF-UCL.
DR GO; GO:0008134; F:transcription factor binding; IPI:UniProtKB.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0006858; P:extracellular transport; IMP:UniProtKB.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISS:BHF-UCL.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; TAS:Reactome.
DR GO; GO:0051224; P:negative regulation of protein transport; IMP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:BHF-UCL.
DR GO; GO:0032410; P:negative regulation of transporter activity; IDA:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; IDA:FlyBase.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0036211; P:protein modification process; TAS:ProtInc.
DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IDA:BHF-UCL.
DR GO; GO:0042391; P:regulation of membrane potential; IDA:BHF-UCL.
DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0046718; P:viral entry into host cell; 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; 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 3D-structure; Alternative splicing; Host-virus interaction; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1..870
FT /note="NEDD4-like E3 ubiquitin-protein ligase WWP2"
FT /id="PRO_0000120338"
FT DOMAIN 1..117
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 300..333
FT /note="WW 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 330..363
FT /note="WW 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 405..437
FT /note="WW 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 444..477
FT /note="WW 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 536..870
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT REGION 151..299
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 151..191
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 198..243
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 838
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT MOD_RES 211
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16964243,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..439
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046461"
FT VAR_SEQ 1..116
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_044706"
FT VAR_SEQ 336..870
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054711"
FT MUTAGEN 498
FT /note="K->R: Does not affect FBXL15-mediated
FT ubiquitination."
FT /evidence="ECO:0000269|PubMed:21572392"
FT MUTAGEN 500
FT /note="H->K: Does not affect FBXL15-mediated
FT ubiquitination."
FT /evidence="ECO:0000269|PubMed:21572392"
FT MUTAGEN 838
FT /note="C->A: Abolishes ubiquitination of POU5F1."
FT /evidence="ECO:0000269|PubMed:19274063"
FT CONFLICT 136
FT /note="E -> K (in Ref. 1; AAC51325)"
FT /evidence="ECO:0000305"
FT CONFLICT 390
FT /note="F -> L (in Ref. 3; BAG62027)"
FT /evidence="ECO:0000305"
FT CONFLICT 394..395
FT /note="SS -> FW (in Ref. 1; AAC51325)"
FT /evidence="ECO:0000305"
FT CONFLICT 545
FT /note="Y -> F (in Ref. 3; BAC86528)"
FT /evidence="ECO:0000305"
FT STRAND 336..340
FT /evidence="ECO:0007829|PDB:6J1Z"
FT STRAND 348..350
FT /evidence="ECO:0007829|PDB:5TJ7"
FT TURN 351..354
FT /evidence="ECO:0007829|PDB:5TJ7"
FT STRAND 355..359
FT /evidence="ECO:0007829|PDB:5TJ7"
FT HELIX 363..386
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 443..445
FT /evidence="ECO:0007829|PDB:6RSS"
FT STRAND 450..454
FT /evidence="ECO:0007829|PDB:6RSS"
FT STRAND 460..464
FT /evidence="ECO:0007829|PDB:6RSS"
FT TURN 465..468
FT /evidence="ECO:0007829|PDB:6RSS"
FT STRAND 469..471
FT /evidence="ECO:0007829|PDB:6RSS"
FT HELIX 477..479
FT /evidence="ECO:0007829|PDB:6RSS"
FT HELIX 495..509
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 512..519
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 521..523
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 524..533
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 537..541
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 542..548
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 556..570
FT /evidence="ECO:0007829|PDB:5TJ8"
FT TURN 574..577
FT /evidence="ECO:0007829|PDB:4Y07"
FT STRAND 579..586
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 588..591
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 595..597
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 601..617
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 628..634
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 641..647
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 649..657
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 674..676
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 683..685
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 691..693
FT /evidence="ECO:0007829|PDB:5TJ8"
FT TURN 698..700
FT /evidence="ECO:0007829|PDB:5TJQ"
FT HELIX 702..712
FT /evidence="ECO:0007829|PDB:5TJ8"
FT TURN 713..716
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 718..731
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 734..737
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 742..750
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 757..762
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 765..768
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 774..785
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 788..799
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 809..811
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 817..819
FT /evidence="ECO:0007829|PDB:5TJ7"
FT STRAND 822..824
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 829..831
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 834..836
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 837..839
FT /evidence="ECO:0007829|PDB:5TJ8"
FT STRAND 841..843
FT /evidence="ECO:0007829|PDB:5TJ8"
FT HELIX 850..862
FT /evidence="ECO:0007829|PDB:5TJ8"
SQ SEQUENCE 870 AA; 98912 MW; FCCD75CBA61F2204 CRC64;
MASASSSRAG VALPFEKSQL TLKVVSAKPK VHNRQPRINS YVEVAVDGLP SETKKTGKRI
GSSELLWNEI IILNVTAQSH LDLKVWSCHT LRNELLGTAS VNLSNVLKNN GGKMENMQLT
LNLQTENKGS VVSGGELTIF LDGPTVDLGN VPNGSALTDG SQLPSRDSSG TAVAPENRHQ
PPSTNCFGGR SRTHRHSGAS ARTTPATGEQ SPGARSRHRQ PVKNSGHSGL ANGTVNDEPT
TATDPEEPSV VGVTSPPAAP LSVTPNPNTT SLPAPATPAE GEEPSTSGTQ QLPAAAQAPD
ALPAGWEQRE LPNGRVYYVD HNTKTTTWER PLPPGWEKRT DPRGRFYYVD HNTRTTTWQR
PTAEYVRNYE QWQSQRNQLQ GAMQHFSQRF LYQSSSASTD HDPLGPLPPG WEKRQDNGRV
YYVNHNTRTT QWEDPRTQGM IQEPALPPGW EMKYTSEGVR YFVDHNTRTT TFKDPRPGFE
SGTKQGSPGA YDRSFRWKYH QFRFLCHSNA LPSHVKISVS RQTLFEDSFQ QIMNMKPYDL
RRRLYIIMRG EEGLDYGGIA REWFFLLSHE VLNPMYCLFE YAGKNNYCLQ INPASSINPD
HLTYFRFIGR FIAMALYHGK FIDTGFTLPF YKRMLNKRPT LKDLESIDPE FYNSIVWIKE
NNLEECGLEL YFIQDMEILG KVTTHELKEG GESIRVTEEN KEEYIMLLTD WRFTRGVEEQ
TKAFLDGFNE VAPLEWLRYF DEKELELMLC GMQEIDMSDW QKSTIYRHYT KNSKQIQWFW
QVVKEMDNEK RIRLLQFVTG TCRLPVGGFA ELIGSNGPQK FCIDKVGKET WLPRSHTCFN
RLDLPPYKSY EQLREKLLYA IEETEGFGQE
