ID ITCH_HUMAN Reviewed; 903 AA. AC Q96J02; A6NEW4; B4E234; E1P5P3; F5H217; O43584; Q5QP37; Q5TEL0; Q96F66; AC Q9BY75; Q9H451; Q9H4U5; DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot. DT 03-OCT-2003, sequence version 2. DT 27-MAR-2024, entry version 209. DE RecName: Full=E3 ubiquitin-protein ligase Itchy homolog; DE Short=Itch; DE EC=2.3.2.26 {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19592251}; DE AltName: Full=Atrophin-1-interacting protein 4; DE Short=AIP4; DE AltName: Full=HECT-type E3 ubiquitin transferase Itchy homolog; DE AltName: Full=NFE2-associated polypeptide 1; DE Short=NAPP1; GN Name=ITCH; 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 2), AND INTERACTION WITH NFE2. RC TISSUE=Leukemia; RX PubMed=11318614; DOI=10.1006/geno.2001.6512; RA Chen X., Wen S.-C., Fukuda M.N., Gavva N.R., Hsu D.-W., Akama T.O., RA Yang-Peng T.L., Shen C.K.J.; RT "Human ITCH is a co-regulator of the hematopoietic transcription factor NF- RT E2."; RL Genomics 73:238-241(2001). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Miyazaki K., Okamoto Y., Sakamoto M., Nakagawara A.; RT "Homo sapiens mRNA for ubiquitin protein ligase Itch, complete cds."; RL Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RC TISSUE=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=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Kidney, 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 NUCLEOTIDE SEQUENCE [MRNA] OF 83-903 (ISOFORM 2), AND INTERACTION WITH RP ATN1. RC TISSUE=Fetal brain; 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 PROTEIN SEQUENCE OF 463-470; 503-510; 514-526; 644-665 AND 875-881, RP INTERACTION WITH LMP2A, AND MUTAGENESIS OF CYS-871. RC TISSUE=B-cell; RX PubMed=11046148; DOI=10.1128/mcb.20.22.8526-8535.2000; RA Winberg G., Matskova L., Chen F., Plant P., Rotin D., Gish G., Ingham R., RA Ernberg I., Pawson T.; RT "Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 RT protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases."; RL Mol. Cell. Biol. 20:8526-8535(2000). RN [9] RP INTERACTION WITH CBLC, AND PHOSPHORYLATION. RX PubMed=12226085; DOI=10.1074/jbc.m206460200; RA Courbard J.-R., Fiore F., Adelaide J., Borg J.P., Birnbaum D., RA Ollendorff V.; RT "Interaction between two ubiquitin-protein isopeptide ligases of different RT classes, CBLC and AIP4/ITCH."; RL J. Biol. Chem. 277:45267-45275(2002). RN [10] RP INTERACTION WITH RNF11. RX PubMed=14559117; DOI=10.1016/j.bbadis.2003.07.001; RA Kitching R., Wong M.J., Koehler D., Burger A.M., Landberg G., Gish G., RA Seth A.K.; RT "The RING-H2 protein RNF11 is differentially expressed in breast tumours RT and interacts with HECT-type E3 ligases."; RL Biochim. Biophys. Acta 1639:104-112(2003). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCATION, INTERACTION RP WITH HGS, AND MUTAGENESIS OF CYS-871. RX PubMed=14602072; DOI=10.1016/s1534-5807(03)00321-6; RA Marchese A., Raiborg C., Santini F., Keen J.H., Stenmark H., Benovic J.L.; RT "The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G RT protein-coupled receptor CXCR4."; RL Dev. Cell 5:709-722(2003). RN [12] RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH NEDD9 AND SMAD3, AND INTERACTION RP WITH NEDD9. RX PubMed=15051726; DOI=10.1074/jbc.m403221200; RA Feng L., Guedes S., Wang T.; RT "Atrophin-1-interacting protein 4/human Itch is a ubiquitin E3 ligase for RT human enhancer of filamentation 1 in transforming growth factor-beta RT signaling pathways."; RL J. Biol. Chem. 279:29681-29690(2004). RN [13] RP PHOSPHORYLATION AT THR-385 AND SER-450, AND INTERACTION WITH SGK3. RX PubMed=16888620; DOI=10.1038/sj.emboj.7601267; RA Slagsvold T., Marchese A., Brech A., Stenmark H.; RT "CISK attenuates degradation of the chemokine receptor CXCR4 via the RT ubiquitin ligase AIP4."; RL EMBO J. 25:3738-3749(2006). RN [14] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH DTX1, AND RP UBIQUITINATION OF DTX1. RX PubMed=17028573; DOI=10.1038/sj.embor.7400822; RA Chastagner P., Israel A., Brou C.; RT "Itch/AIP4 mediates Deltex degradation through the formation of K29-linked RT polyubiquitin chains."; RL EMBO Rep. 7:1147-1153(2006). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH JUNB AND FYN, RP PHOSPHORYLATION AT TYR-420, IDENTIFICATION BY MASS SPECTROMETRY, AND RP MUTAGENESIS OF TYR-343; TYR-420 AND TYR-455. RX PubMed=16387660; DOI=10.1016/j.molcel.2005.11.014; RA Yang C., Zhou W., Jeon M.S., Demydenko D., Harada Y., Zhou H., Liu Y.C.; RT "Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated RT tyrosine phosphorylation."; RL Mol. Cell 21:135-141(2006). RN [16] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND INTERACTION WITH NFE2. RX PubMed=18718448; DOI=10.1016/j.bbrc.2008.07.164; RA Lee T.-L., Shyu Y.-C., Hsu T.-Y., Shen C.-K.J.; RT "Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination."; RL Biochem. Biophys. Res. Commun. 375:326-330(2008). RN [17] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AUTOUBIQUITINATION, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=18718449; DOI=10.1016/j.bcp.2008.07.028; RA Scialpi F., Malatesta M., Peschiaroli A., Rossi M., Melino G., RA Bernassola F.; RT "Itch self-polyubiquitylation occurs through lysine-63 linkages."; RL Biochem. Pharmacol. 76:1515-1521(2008). RN [18] RP SUBCELLULAR LOCATION. RX PubMed=18819914; DOI=10.1074/jbc.m804120200; RA Putz U., Howitt J., Lackovic J., Foot N., Kumar S., Silke J., Tan S.S.; RT "Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal RT secretion of Nedd4 family proteins."; RL J. Biol. Chem. 283:32621-32627(2008). RN [19] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND UBIQUITINATION OF NOTCH1. RX PubMed=18628966; DOI=10.1371/journal.pone.0002735; RA Chastagner P., Israel A., Brou C.; RT "AIP4/Itch regulates Notch receptor degradation in the absence of ligand."; RL PLoS ONE 3:E2735-E2735(2008). RN [20] RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [21] RP INTERACTION WITH SPART. RX PubMed=19580544; DOI=10.1042/bj20082398; RA Edwards T.L., Clowes V.E., Tsang H.T., Connell J.W., Sanderson C.M., RA Luzio J.P., Reid E.; RT "Endogenous spartin (SPG20) is recruited to endosomes and lipid droplets RT and interacts with the ubiquitin E3 ligases AIP4 and AIP5."; RL Biochem. J. 423:31-39(2009). RN [22] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND UBIQUITINATION OF RIPK2. RX PubMed=19592251; DOI=10.1016/j.cub.2009.06.038; RA Tao M., Scacheri P.C., Marinis J.M., Harhaj E.W., Matesic L.E., RA Abbott D.W.; RT "ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence RT inflammatory signaling pathways."; RL Curr. Biol. 19:1255-1263(2009). RN [23] RP FUNCTION, AND INTERACTION WITH RNF11. RX PubMed=19131965; DOI=10.1038/emboj.2008.285; RA Shembade N., Parvatiyar K., Harhaj N.S., Harhaj E.W.; RT "The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB RT signalling."; RL EMBO J. 28:513-522(2009). RN [24] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH CXCR4, AND RP UBIQUITINATION. RX PubMed=19116316; DOI=10.1091/mbc.e08-03-0308; RA Bhandari D., Robia S.L., Marchese A.; RT "The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to RT the chemokine receptor CXCR4 via a novel WW domain-mediated interaction."; RL Mol. Biol. Cell 20:1324-1339(2009). RN [25] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, UBIQUITINATION OF MAVS, INTERACTION RP WITH PCBP2, AND MUTAGENESIS OF CYS-871. RX PubMed=19881509; DOI=10.1038/ni.1815; RA You F., Sun H., Zhou X., Sun W., Liang S., Zhai Z., Jiang Z.; RT "PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin RT ligase AIP4."; RL Nat. Immunol. 10:1300-1308(2009). RN [26] RP INVOLVEMENT IN ADMFD. RX PubMed=20170897; DOI=10.1016/j.ajhg.2010.01.028; RA Lohr N.J., Molleston J.P., Strauss K.A., Torres-Martinez W., Sherman E.A., RA Squires R.H., Rider N.L., Chikwava K.R., Cummings O.W., Morton D.H., RA Puffenberger E.G.; RT "Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem RT autoimmune disease."; RL Am. J. Hum. Genet. 86:447-453(2010). RN [27] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH SNX9 AND SNX18, AND RP UBIQUITINATION OF SNX9. RX PubMed=20491914; DOI=10.1111/j.1742-4658.2010.07698.x; RA Baumann C., Lindholm C.K., Rimoldi D., Levy F.; RT "The E3 ubiquitin ligase Itch regulates sorting nexin 9 through an RT unconventional substrate recognition domain."; RL FEBS J. 277:2803-2814(2010). RN [28] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH P15 BID, AND RP UBIQUITINATION OF P15 BID. RX PubMed=20392206; DOI=10.1111/j.1742-4658.2010.07562.x; RA Azakir B.A., Desrochers G., Angers A.; RT "The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal RT growth factor by promoting the ubiquitylation and degradation of the RT truncated C-terminal portion of Bid."; RL FEBS J. 277:1319-1330(2010). RN [29] RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH TXNIP, AND RP UBIQUITINATION OF TXNIP. RX PubMed=20068034; DOI=10.1074/jbc.m109.063321; RA Zhang P., Wang C., Gao K., Wang D., Mao J., An J., Xu C., Wu D., Yu H., RA Liu J.O., Yu L.; RT "The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin- RT interacting protein for ubiquitin-dependent degradation."; RL J. Biol. Chem. 285:8869-8879(2010). RN [30] 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 [31] RP FUNCTION, AND INTERACTION WITH HERPES SIMPLEX VIRUS 2 PROTEIN UL56. RX PubMed=20682038; DOI=10.1186/1743-422x-7-179; RA Ushijima Y., Luo C., Kamakura M., Goshima F., Kimura H., Nishiyama Y.; RT "Herpes simplex virus UL56 interacts with and regulates the Nedd4-family RT ubiquitin ligase Itch."; RL Virol. J. 7:179-179(2010). RN [32] 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 [33] 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 [34] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, INTERACTION RP WITH PI4K2A, SUBCELLULAR LOCATION, UBIQUITINATION, AND MUTAGENESIS OF RP CYS-871. RX PubMed=23146885; DOI=10.1038/embor.2012.164; RA Mossinger J., Wieffer M., Krause E., Freund C., Gerth F., Krauss M., RA Haucke V.; RT "Phosphatidylinositol 4-kinase IIalpha function at endosomes is regulated RT by the ubiquitin ligase Itch."; RL EMBO Rep. 13:1087-1094(2012). RN [35] RP INTERACTION WITH OTUD7B. RX PubMed=22179831; DOI=10.1038/onc.2011.587; RA Pareja F., Ferraro D.A., Rubin C., Cohen-Dvashi H., Zhang F., Aulmann S., RA Ben-Chetrit N., Pines G., Navon R., Crosetto N., Kostler W., Carvalho S., RA Lavi S., Schmitt F., Dikic I., Yakhini Z., Sinn P., Mills G.B., Yarden Y.; RT "Deubiquitination of EGFR by Cezanne-1 contributes to cancer progression."; RL Oncogene 31:4599-4608(2012). RN [36] 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 [37] RP FUNCTION, AND INTERACTION WITH ARRDC1 AND ARRDC3. RX PubMed=23886940; DOI=10.1242/jcs.130500; RA Puca L., Chastagner P., Meas-Yedid V., Israel A., Brou C.; RT "Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch RT degradation in mammals."; RL J. Cell Sci. 126:4457-4468(2013). RN [38] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, INTERACTION RP WITH DTX3L, IDENTIFICATION IN A COMPLEX WITH DTX3L; STAM AND HGS, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-871. RX PubMed=24790097; DOI=10.1091/mbc.e13-10-0612; RA Holleman J., Marchese A.; RT "The ubiquitin ligase deltex-3l regulates endosomal sorting of the G RT protein-coupled receptor CXCR4."; RL Mol. Biol. Cell 25:1892-1904(2014). RN [39] RP FUNCTION IN UBIQUITINATION OF BRAT1, CATALYTIC ACTIVITY, ACTIVITY RP REGULATION, AND PATHWAY. RX PubMed=25631046; DOI=10.1074/jbc.m114.613687; RA Low L.H., Chow Y.L., Li Y., Goh C.P., Putz U., Silke J., Ouchi T., RA Howitt J., Tan S.S.; RT "Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination RT and nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during RT the DNA damage response."; RL J. Biol. Chem. 290:7141-7150(2015). RN [40] RP INTERACTION WITH UBE2L3. RX PubMed=25632008; DOI=10.4049/jimmunol.1402742; RA Kathania M., Zeng M., Yadav V.N., Moghaddam S.J., Yang B., Venuprasad K.; RT "Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7."; RL J. Immunol. 194:2160-2167(2015). RN [41] RP INTERACTION WITH LDLRAD3. RX PubMed=26854353; DOI=10.1021/acs.biochem.5b01218; RA Noyes N.C., Hampton B., Migliorini M., Strickland D.K.; RT "Regulation of Itch and Nedd4 E3 Ligase Activity and Degradation by RT LRAD3."; RL Biochemistry 55:1204-1213(2016). RN [42] RP INTERACTION WITH EBOLA VIRUS PROTEIN VP40 (MICROBIAL INFECTION). RX PubMed=27489272; DOI=10.1128/jvi.01078-16; RA Han Z., Sagum C.A., Bedford M.T., Sidhu S.S., Sudol M., Harty R.N.; RT "ITCH E3 Ubiquitin Ligase Interacts with Ebola Virus VP40 To Regulate RT Budding."; RL J. Virol. 90:9163-9171(2016). RN [43] RP INTERACTION WITH HCMV PROTEIN UL42 (MICROBIAL INFECTION). RX PubMed=26555021; DOI=10.1099/jgv.0.000336; RA Koshizuka T., Tanaka K., Suzutani T.; RT "Degradation of host ubiquitin E3 ligase Itch by human cytomegalovirus RT UL42."; RL J. Gen. Virol. 97:196-208(2016). RN [44] RP INTERACTION WITH HUMAN HERPESVIRUS 8 PROTEIN RTA/ORF50 (MICROBIAL RP INFECTION). RX PubMed=27912080; DOI=10.1016/j.virol.2016.11.016; RA Chmura J.C., Herold K., Ruffin A., Atuobi T., Fabiyi Y., Mitchell A.E., RA Choi Y.B., Ehrlich E.S.; RT "The Itch ubiquitin ligase is required for KSHV RTA induced vFLIP RT degradation."; RL Virology 501:119-126(2017). RN [45] RP INTERACTION WITH HHV-1 UL56 (MICROBIAL INFECTION), INTERACTION WITH VZV RP ORF0 (MICROBIAL INFECTION), INTERACTION WITH HCMV UL42 (MICROBIAL RP INFECTION), AND INTERACTION WITH HHV-6A U24 (MICROBIAL INFECTION). RX PubMed=29535361; DOI=10.1038/s41598-018-22682-2; RA Koshizuka T., Kobayashi T., Ishioka K., Suzutani T.; RT "Herpesviruses possess conserved proteins for interaction with Nedd4 family RT ubiquitin E3 ligases."; RL Sci. Rep. 8:4447-4447(2018). RN [46] RP FUNCTION, AND INTERACTION WITH INFLUENZA A VIRUS MATRIX PROTEIN 1 RP (MICROBIAL INFECTION). RX PubMed=30328013; DOI=10.1007/s12250-018-0058-6; RA Mahesutihan M., Zheng W., Cui L., Li Y., Jiao P., Yang W., Liu W., Li J., RA Fan W., Yang L., Liu W., Sun L.; RT "CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus."; RL Virol. Sin. 33:440-448(2018). RN [47] RP FUNCTION, INTERACTION WITH ENTREP1, AND DOMAIN. RX PubMed=34927784; DOI=10.15252/embr.202051182; RA Tsunoda T., Riku M., Yamada N., Tsuchiya H., Tomita T., Suzuki M., RA Kizuki M., Inoko A., Ito H., Murotani K., Murakami H., Saeki Y., Kasai K.; RT "ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is RT downregulated in breast cancer."; RL EMBO Rep. 23:e51182-e51182(2022). RN [48] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 246-270 IN COMPLEX WITH ARHGEF7. RX PubMed=17652093; DOI=10.1074/jbc.m702678200; RA Janz J.M., Sakmar T.P., Min K.C.; RT "A novel interaction between atrophin-interacting protein 4 and beta-p21- RT activated kinase-interactive exchange factor is mediated by an SH3 RT domain."; RL J. Biol. Chem. 282:28893-28903(2007). RN [49] RP STRUCTURE BY NMR OF 328-357. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the second WW domain of ITCHY homolog E3 ubiquitin RT protein ligase (ITCH)."; RL Submitted (OCT-2006) to the PDB data bank. CC -!- FUNCTION: Acts as an E3 ubiquitin-protein ligase which accepts CC ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a CC thioester and then directly transfers the ubiquitin to targeted CC substrates (PubMed:14602072, PubMed:17028573, PubMed:16387660, CC PubMed:18718448, PubMed:18718449, PubMed:11046148, PubMed:19592251, CC PubMed:19116316, PubMed:19881509, PubMed:20491914, PubMed:20392206, CC PubMed:20068034, PubMed:23146885, PubMed:24790097, PubMed:25631046, CC PubMed:15051726). Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked CC ubiquitin conjugation (PubMed:17028573, PubMed:18718448, CC PubMed:19131965, PubMed:19881509). Involved in the control of CC inflammatory signaling pathways (PubMed:19131965). Essential component CC of a ubiquitin-editing protein complex, comprising also TNFAIP3, CC TAX1BP1 and RNF11, that ensures the transient nature of inflammatory CC signaling pathways (PubMed:19131965). Promotes the association of the CC complex after TNF stimulation (PubMed:19131965). Once the complex is CC formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 CC and catalyzes the formation of 'Lys-48'-polyubiquitin chains CC (PubMed:19131965). This leads to RIPK1 proteasomal degradation and CC consequently termination of the TNF- or LPS-mediated activation of CC NFKB1 (PubMed:19131965). Ubiquitinates RIPK2 by 'Lys-63'-linked CC conjugation and influences NOD2-dependent signal transduction pathways CC (PubMed:19592251). Regulates the transcriptional activity of several CC transcription factors, and probably plays an important role in the CC regulation of immune response (PubMed:18718448, PubMed:20491914). CC Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the CC control of the development of hematopoietic lineages (PubMed:18718448). CC Mediates JUN ubiquitination and degradation (By similarity). Mediates CC JUNB ubiquitination and degradation (PubMed:16387660). Critical CC regulator of type 2 helper T (Th2) cell cytokine production by inducing CC JUNB ubiquitination and degradation (By similarity). Involved in the CC negative regulation of MAVS-dependent cellular antiviral responses CC (PubMed:19881509). Ubiquitinates MAVS through 'Lys-48'-linked CC conjugation resulting in MAVS proteasomal degradation CC (PubMed:19881509). Following ligand stimulation, regulates sorting of CC Wnt receptor FZD4 to the degradative endocytic pathway probably by CC modulating PI42KA activity (PubMed:23146885). Ubiquitinates PI4K2A and CC negatively regulates its catalytic activity (PubMed:23146885). CC Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 CC to the degradative endocytic pathway following ligand stimulation by CC ubiquitinating endosomal sorting complex required for transport ESCRT-0 CC components HGS and STAM (PubMed:14602072, PubMed:23146885, CC PubMed:34927784). Targets DTX1 for lysosomal degradation and controls CC NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked CC polyubiquitination (PubMed:17028573, PubMed:18628966, PubMed:23886940). CC Ubiquitinates SNX9 (PubMed:20491914). Ubiquitinates MAP3K7 through CC 'Lys-48'-linked conjugation (By similarity). Involved in the regulation CC of apoptosis and reactive oxygen species levels through the CC ubiquitination and proteasomal degradation of TXNIP (PubMed:20068034). CC Mediates the antiapoptotic activity of epidermal growth factor through CC the ubiquitination and proteasomal degradation of p15 BID CC (PubMed:20392206). Ubiquitinates BRAT1 and this ubiquitination is CC enhanced in the presence of NDFIP1 (PubMed:25631046). Inhibits the CC replication of influenza A virus (IAV) via ubiquitination of IAV matrix CC protein 1 (M1) through 'Lys-48'-linked conjugation resulting in M1 CC proteasomal degradation (PubMed:30328013). Ubiquitinates NEDD9/HEF1, CC resulting in proteasomal degradation of NEDD9/HEF1 (PubMed:15051726). CC {ECO:0000250|UniProtKB:Q8C863, ECO:0000269|PubMed:14602072, CC ECO:0000269|PubMed:15051726, ECO:0000269|PubMed:16387660, CC ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966, CC ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449, CC ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:19131965, CC ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19881509, CC ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206, CC ECO:0000269|PubMed:20491914, ECO:0000269|PubMed:23146885, CC ECO:0000269|PubMed:23886940, ECO:0000269|PubMed:24790097, CC ECO:0000269|PubMed:25631046, ECO:0000269|PubMed:30328013}. 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:14602072, CC ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:17028573, CC ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:18718448, CC ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19116316, CC ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19881509, CC ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206, CC ECO:0000269|PubMed:20491914, ECO:0000269|PubMed:23146885, CC ECO:0000269|PubMed:24790097, ECO:0000269|PubMed:25631046}; CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding CC (PubMed:25631046). Activated by PI4K2A-binding (PubMed:23146885). CC Inhibited by DTX3L-binding (PubMed:24790097). Inhibited by N4BP1 CC binding (By similarity). {ECO:0000250|UniProtKB:Q8C863, CC ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097, CC ECO:0000269|PubMed:25631046}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:16387660, CC ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966, CC ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449, CC ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:19592251, CC ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:20068034, CC ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:20491914, CC ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097, CC ECO:0000269|PubMed:25631046}. CC -!- SUBUNIT: Monomer. Part of a ternary complex composed of SMAD3, CC ITCH/AIP4 and NEDD9/HEF1; within the complex NEDD9/HEF1 interacts (via CC N-terminus) with ITCH/AIP4 (via WW domains); the complex mediates CC ubiquitination and proteasomal degradation of NEDD9/HEF1 CC (PubMed:15051726). Interacts (via WW domains) with OCNL (By CC similarity). Interacts (via WW domains) with NOTCH1 (By similarity). CC Interacts (via WW domains) with JUN (By similarity). Interacts with CC JUNB; the interaction promotes ITCH-mediated ubiquitination and CC degradation of JUNB (PubMed:16387660). Interacts with FYN; the CC interaction phosphorylates ITCH on Tyr-420 decreasing binding of JUNB CC (PubMed:16387660). Interacts (via WW domain 2) with N4BP1; the CC interaction inhibits the E3 ubiquitin-protein ligase activity (By CC similarity). Interacts with NDFIP1 and NDFIP2; this interaction CC activates the E3 ubiquitin-protein ligase and may induce its CC recruitment to exosomes (By similarity). Interacts with ARHGEF7 CC (PubMed:17652093). Interacts with RNF11 (PubMed:14559117, CC PubMed:19131965). Interacts (via the WW 1 domain) with NFE2 (via the CC PXY motif 1); the interaction promotes 'Lys-63'-linked ubiquitination CC of NFE2, retains it in the cytoplasm and prevents its transactivation CC activity (PubMed:11318614, PubMed:18718448). Interacts (via WW domains) CC with CXCR4 (via C-terminus); the interaction depends on CXCR4 CC phosphorylation (PubMed:19116316). Found in a complex with E3 ligase CC DTX3L and ESCRT-0 components HGS and STAM (PubMed:24790097). Interacts CC with DTX3L (via C-terminus); the interaction is increased upon CXCL12 CC stimulation and inhibits ITCH catalytic activity (the interaction is CC direct) (PubMed:24790097). Interacts with HGS (PubMed:14602072). CC Interacts (via WW domains) with PCBP2 within a complex containing ITCH, CC MAVS and PCBP2 (PubMed:19881509). Interacts (via WW domains) with TXNIP CC (via C-terminus) (PubMed:20068034). Interacts with p15 BID CC (PubMed:20392206). Interacts with ERBB4 (PubMed:20858735). Interacts CC with DTX1 (PubMed:17028573). Interacts with SPART (PubMed:19580544). CC Interacts with SNX9 and SNX18 (PubMed:20491914). Interacts (via its WW CC domains) with ATN1 (PubMed:9647693). Interacts (via WW domains) with CC SGK3 (PubMed:16888620). Interacts with CBLC (PubMed:12226085). CC Interacts with OTUD7B (PubMed:22179831). Interacts (via WW domain 1,2 CC and 3) with PI4K2A; the interaction inhibits PI4K2A catalytic activity CC and promotes ITCH catalytic activity (PubMed:23146885). Interacts with CC ARRDC4 (PubMed:23236378). Part of a complex containing ITCH, NDFIP1 and CC MAP3K7 (By similarity). Interacts with UBE2L3; the interaction is CC mediated by NDFIP1 (PubMed:25632008). Interacts with MAPK8/JNK1 (By CC similarity). Interacts (via WW domains) with ARRDC1 (via PPxY motifs); CC the interaction is direct and participates in the recruitment of the CC ubiquitin-protein ligase ITCH to the NOTCH1 receptor (PubMed:21191027, CC PubMed:23886940). Interacts (via WW domains) with ARRDC2 CC (PubMed:21191027). Interacts (via WW domains) with ARRDC3 CC (PubMed:21191027, PubMed:23886940). Interacts directly with LDLRAD3; CC this interaction promotes ITCH auto-ubiquitination leading to its CC degradation (PubMed:26854353). Interacts with ENTREP1; enhances the CC ubiquitination of CXCR4 by ITCH and its subsequent endocytosis CC (PubMed:34927784). {ECO:0000250|UniProtKB:Q8C863, CC ECO:0000269|PubMed:11318614, ECO:0000269|PubMed:12226085, CC ECO:0000269|PubMed:14559117, ECO:0000269|PubMed:14602072, CC ECO:0000269|PubMed:15051726, ECO:0000269|PubMed:16387660, CC ECO:0000269|PubMed:16888620, ECO:0000269|PubMed:17028573, CC ECO:0000269|PubMed:17652093, ECO:0000269|PubMed:18718448, CC ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:19131965, CC ECO:0000269|PubMed:19580544, ECO:0000269|PubMed:19881509, CC ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206, CC ECO:0000269|PubMed:20491914, ECO:0000269|PubMed:20858735, CC ECO:0000269|PubMed:21191027, ECO:0000269|PubMed:22179831, CC ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:23236378, CC ECO:0000269|PubMed:23886940, ECO:0000269|PubMed:24790097, CC ECO:0000269|PubMed:25632008, ECO:0000269|PubMed:26854353, CC ECO:0000269|PubMed:34927784, ECO:0000269|PubMed:9647693}. CC -!- SUBUNIT: (Microbial infection) Interacts with Epstein-Barr virus LMP2A. CC {ECO:0000269|PubMed:11046148}. CC -!- SUBUNIT: (Microbial infection) Interacts with Human cytomegalovirus CC (HCMV) protein UL42; this interaction induces ubiquitination and CC degradation of ITCH. {ECO:0000269|PubMed:26555021, CC ECO:0000269|PubMed:29535361}. CC -!- SUBUNIT: (Microbial infection) Interacts with herpesvirus 1 (HHV-1) CC UL56 protein; this interaction induces ubiquitination and probably CC degradation of ITCH. {ECO:0000269|PubMed:29535361}. CC -!- SUBUNIT: (Microbial infection) Interacts with herpesvirus 2 (HHV-2) CC UL56 protein. {ECO:0000269|PubMed:20682038}. CC -!- SUBUNIT: (Microbial infection) Interacts with varicella-zoster virus CC (VZV) Orf0 protein. {ECO:0000269|PubMed:29535361}. CC -!- SUBUNIT: (Microbial infection) Interacts with herpesvirus 6A (HHV-6A) CC U24 protein. {ECO:0000269|PubMed:29535361}. CC -!- SUBUNIT: (Microbial infection) Interacts with ebola virus protein VP40; CC this interaction is required for efficient viral egress from the CC infected cell. {ECO:0000269|PubMed:27489272}. CC -!- SUBUNIT: (Microbial infection) Interacts with influenza A virus matrix CC protein 1. {ECO:0000269|PubMed:30328013}. CC -!- SUBUNIT: (Microbial infection) Interacts with human herpesvirus 8 CC (KSHV) protein RTA/ORF50; this interaction targets viral vFLIP for CC proteasomal degradation. {ECO:0000269|PubMed:27912080}. CC -!- INTERACTION: CC Q96J02; Q96B67: ARRDC3; NbExp=3; IntAct=EBI-1564678, EBI-2875665; CC Q96J02; Q9NQC7: CYLD; NbExp=3; IntAct=EBI-1564678, EBI-2117940; CC Q96J02; P08151: GLI1; NbExp=4; IntAct=EBI-1564678, EBI-308084; CC Q96J02; Q16655: MLANA; NbExp=2; IntAct=EBI-1564678, EBI-2509726; CC Q96J02; O75113: N4BP1; NbExp=3; IntAct=EBI-1564678, EBI-5278391; CC Q96J02; Q9BTU6: PI4K2A; NbExp=5; IntAct=EBI-1564678, EBI-3239392; CC Q96J02; Q9Y3C5: RNF11; NbExp=2; IntAct=EBI-1564678, EBI-396669; CC Q96J02; Q96BR1: SGK3; NbExp=5; IntAct=EBI-1564678, EBI-2801236; CC Q96J02; Q9Y5X1: SNX9; NbExp=7; IntAct=EBI-1564678, EBI-77848; CC Q96J02; Q9NW97: TMEM51; NbExp=3; IntAct=EBI-1564678, EBI-726044; CC Q96J02; Q13625: TP53BP2; NbExp=2; IntAct=EBI-1564678, EBI-77642; CC Q96J02; Q9H3D4: TP63; NbExp=2; IntAct=EBI-1564678, EBI-2337775; CC Q96J02; O15350: TP73; NbExp=5; IntAct=EBI-1564678, EBI-389606; CC Q96J02; O15350-1: TP73; NbExp=5; IntAct=EBI-1564678, EBI-389619; CC Q96J02; O15350-8: TP73; NbExp=2; IntAct=EBI-1564678, EBI-5651259; CC Q96J02; Q9C0H2: TTYH3; NbExp=2; IntAct=EBI-1564678, EBI-2116541; CC Q96J02; P13285: LMP2; Xeno; NbExp=3; IntAct=EBI-1564678, EBI-7181113; CC Q96J02; P03519: M; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-7228115; CC Q96J02; P04876: M; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40246327; CC Q96J02; Q5K2K5: M; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40246199; CC Q96J02; Q8B0H2: M; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40246300; CC Q96J02; Q8B0H7: M; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40246273; CC Q96J02; Q8B0I2: M; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40246247; CC Q96J02; Q9QZS3-2: Numb; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-3896014; CC Q96J02; P35260: VP40; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40244030; CC Q96J02; Q03040: VP40; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40244005; CC Q96J02; Q1PD51: VP40; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40243977; CC Q96J02; Q1PDC8: VP40; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40243950; CC Q96J02; Q5XX06: VP40; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-38773572; CC Q96J02; Q6UY67: VP40; Xeno; NbExp=2; IntAct=EBI-1564678, EBI-40243922; CC Q96J02-2; P61073: CXCR4; NbExp=3; IntAct=EBI-6672198, EBI-489411; CC Q96J02-2; Q9NQC7: CYLD; NbExp=2; IntAct=EBI-6672198, EBI-2117940; CC Q96J02-2; Q15884: ENTREP1; NbExp=6; IntAct=EBI-6672198, EBI-8636612; CC Q96J02-2; Q15303: ERBB4; NbExp=3; IntAct=EBI-6672198, EBI-80371; CC Q96J02-2; Q15303-3: ERBB4; NbExp=2; IntAct=EBI-6672198, EBI-15692884; CC Q96J02-2; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-6672198, EBI-1055254; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14602072}; CC Peripheral membrane protein {ECO:0000305|PubMed:14602072}; Cytoplasmic CC side {ECO:0000305|PubMed:14602072}. Cytoplasm CC {ECO:0000269|PubMed:14602072}. Nucleus {ECO:0000269|PubMed:20858735}. CC Early endosome membrane {ECO:0000269|PubMed:14602072, CC ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097}; Peripheral CC membrane protein {ECO:0000305|PubMed:14602072, CC ECO:0000305|PubMed:23146885, ECO:0000305|PubMed:24790097}; Cytoplasmic CC side {ECO:0000305|PubMed:14602072, ECO:0000305|PubMed:23146885, CC ECO:0000305|PubMed:24790097}. Endosome membrane CC {ECO:0000269|PubMed:23146885}; Peripheral membrane protein CC {ECO:0000305|PubMed:23146885}; Cytoplasmic side CC {ECO:0000305|PubMed:23146885}. Note=May be recruited to exosomes by CC NDFIP1 (PubMed:18819914). Localizes to plasma membrane upon CXCL12 CC stimulation where it co-localizes with CXCL4 (PubMed:14602072). CC Localization to early endosomes is increased upon CXCL12 stimulation CC where it co-localizes with DTX3L and CXCL4 (PubMed:24790097). CC {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:18819914, CC ECO:0000269|PubMed:24790097}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q96J02-1; Sequence=Displayed; CC Name=2; CC IsoId=Q96J02-2; Sequence=VSP_008451; CC Name=3; CC IsoId=Q96J02-3; Sequence=VSP_044732, VSP_008451; CC -!- TISSUE SPECIFICITY: Widely expressed. CC -!- DOMAIN: The WW domains mediate interaction with PPxY motif-containing CC proteins. {ECO:0000269|PubMed:21191027, ECO:0000269|PubMed:34927784}. CC -!- DOMAIN: The WW domain 4 mediates interaction with ENTREP1. CC {ECO:0000269|PubMed:34927784}. CC -!- PTM: On T-cell activation, phosphorylation by the JNK cascade on serine CC and threonine residues surrounding the PRR domain accelerates the CC ubiquitination and degradation of JUN and JUNB. The increased ITCH CC catalytic activity due to phosphorylation by JNK1 may occur due to a CC conformational change disrupting the interaction between the PRR/WW CC motifs domain and the HECT domain and, thus exposing the HECT domain CC (By similarity). Phosphorylation by FYN reduces interaction with JUNB CC and negatively controls JUN ubiquitination and degradation. CC {ECO:0000250, ECO:0000269|PubMed:12226085, ECO:0000269|PubMed:16387660, CC ECO:0000269|PubMed:16888620, ECO:0000269|PubMed:18718449}. CC -!- PTM: Monoubiquitinated (PubMed:19116316). Autopolyubiquitinated with CC 'Lys-63' linkages which does not lead to protein degradation CC (PubMed:18718449, PubMed:23146885, PubMed:24790097). CC {ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19116316, CC ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097}. CC -!- DISEASE: Autoimmune disease, multisystem, with facial dysmorphism CC (ADMFD) [MIM:613385]: A disorder characterized by organomegaly, failure CC to thrive, developmental delay, dysmorphic features and autoimmune CC inflammatory cell infiltration of the lungs, liver and gut. CC {ECO:0000269|PubMed:20170897}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF095745; AAK39399.1; -; mRNA. DR EMBL; AB056663; BAB39389.1; -; mRNA. DR EMBL; AK304090; BAG64996.1; -; mRNA. DR EMBL; AK315212; BAG37647.1; -; mRNA. DR EMBL; AL109923; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL356299; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471077; EAW76272.1; -; Genomic_DNA. DR EMBL; CH471077; EAW76274.1; -; Genomic_DNA. DR EMBL; CH471077; EAW76276.1; -; Genomic_DNA. DR EMBL; BC006848; AAH06848.1; -; mRNA. DR EMBL; BC011571; AAH11571.1; -; mRNA. DR EMBL; AF038564; AAC04845.1; -; mRNA. DR CCDS; CCDS13234.1; -. [Q96J02-2] DR CCDS; CCDS58768.1; -. [Q96J02-1] DR CCDS; CCDS58769.1; -. [Q96J02-3] DR RefSeq; NP_001244066.1; NM_001257137.2. [Q96J02-1] DR RefSeq; NP_001244067.1; NM_001257138.2. [Q96J02-3] DR RefSeq; NP_001311126.1; NM_001324197.1. [Q96J02-1] DR RefSeq; NP_001311127.1; NM_001324198.1. [Q96J02-2] DR RefSeq; NP_113671.3; NM_031483.6. [Q96J02-2] DR RefSeq; XP_016883578.1; XM_017028089.1. [Q96J02-1] DR RefSeq; XP_016883580.1; XM_017028091.1. DR PDB; 2DMV; NMR; -; A=328-357. DR PDB; 2KYK; NMR; -; A=359-392. DR PDB; 2NQ3; X-ray; 1.80 A; A=1-155. DR PDB; 2P4R; X-ray; 2.00 A; T=246-270. DR PDB; 2YSF; NMR; -; A=480-512. DR PDB; 3TUG; X-ray; 2.27 A; A=524-903. DR PDB; 4ROF; X-ray; 2.03 A; A/B=436-474. DR PDB; 5C7M; X-ray; 3.03 A; A=524-899. DR PDB; 5CQ2; X-ray; 1.40 A; A=433-521. DR PDB; 5DWS; X-ray; 1.65 A; A/C/E/G=436-474. DR PDB; 5DZD; X-ray; 1.57 A; A/B=475-514. DR PDB; 5SXP; X-ray; 1.65 A; F/G=249-269. DR PDBsum; 2DMV; -. DR PDBsum; 2KYK; -. DR PDBsum; 2NQ3; -. DR PDBsum; 2P4R; -. DR PDBsum; 2YSF; -. DR PDBsum; 3TUG; -. DR PDBsum; 4ROF; -. DR PDBsum; 5C7M; -. DR PDBsum; 5CQ2; -. DR PDBsum; 5DWS; -. DR PDBsum; 5DZD; -. DR PDBsum; 5SXP; -. DR AlphaFoldDB; Q96J02; -. DR SMR; Q96J02; -. DR BioGRID; 123747; 329. DR CORUM; Q96J02; -. DR DIP; DIP-29849N; -. DR ELM; Q96J02; -. DR IntAct; Q96J02; 105. DR MINT; Q96J02; -. DR STRING; 9606.ENSP00000499786; -. DR ChEMBL; CHEMBL4295925; -. DR GlyGen; Q96J02; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q96J02; -. DR PhosphoSitePlus; Q96J02; -. DR SwissPalm; Q96J02; -. DR BioMuta; ITCH; -. DR DMDM; 37537897; -. DR EPD; Q96J02; -. DR jPOST; Q96J02; -. DR MassIVE; Q96J02; -. DR MaxQB; Q96J02; -. DR PaxDb; 9606-ENSP00000480499; -. DR PeptideAtlas; Q96J02; -. DR ProteomicsDB; 25826; -. DR ProteomicsDB; 76882; -. [Q96J02-1] DR ProteomicsDB; 76883; -. [Q96J02-2] DR Pumba; Q96J02; -. DR Antibodypedia; 10897; 393 antibodies from 42 providers. DR CPTC; Q96J02; 3 antibodies. DR DNASU; 83737; -. DR Ensembl; ENST00000262650.11; ENSP00000262650.5; ENSG00000078747.17. [Q96J02-1] DR Ensembl; ENST00000374864.10; ENSP00000363998.4; ENSG00000078747.17. [Q96J02-2] DR Ensembl; ENST00000535650.8; ENSP00000445608.1; ENSG00000078747.17. [Q96J02-3] DR Ensembl; ENST00000665346.1; ENSP00000499786.1; ENSG00000078747.17. [Q96J02-1] DR Ensembl; ENST00000696974.1; ENSP00000513011.1; ENSG00000078747.17. [Q96J02-2] DR GeneID; 83737; -. DR KEGG; hsa:83737; -. DR MANE-Select; ENST00000374864.10; ENSP00000363998.4; NM_031483.7; NP_113671.3. [Q96J02-2] DR UCSC; uc002xak.3; human. [Q96J02-1] DR AGR; HGNC:13890; -. DR CTD; 83737; -. DR DisGeNET; 83737; -. DR GeneCards; ITCH; -. DR HGNC; HGNC:13890; ITCH. DR HPA; ENSG00000078747; Low tissue specificity. DR MalaCards; ITCH; -. DR MIM; 606409; gene. DR MIM; 613385; phenotype. DR neXtProt; NX_Q96J02; -. DR OpenTargets; ENSG00000078747; -. DR Orphanet; 228426; Syndromic multisystem autoimmune disease due to Itch deficiency. DR PharmGKB; PA29934; -. DR VEuPathDB; HostDB:ENSG00000078747; -. DR eggNOG; KOG0940; Eukaryota. DR GeneTree; ENSGT00940000157014; -. DR HOGENOM; CLU_002173_0_1_1; -. DR InParanoid; Q96J02; -. DR OMA; DNYTIQI; -. DR OrthoDB; 5480520at2759; -. DR PhylomeDB; Q96J02; -. DR TreeFam; TF323658; -. DR BRENDA; 2.3.2.26; 2681. DR BRENDA; 2.3.2.B8; 2681. DR PathwayCommons; Q96J02; -. DR Reactome; R-HSA-1253288; Downregulation of ERBB4 signaling. DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-5610780; Degradation of GLI1 by the proteasome. DR Reactome; R-HSA-5632684; Hedgehog 'on' state. DR Reactome; R-HSA-5675482; Regulation of necroptotic cell death. DR Reactome; R-HSA-8939236; RUNX1 regulates transcription of genes involved in differentiation of HSCs. DR Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling. DR Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q96J02; -. DR SIGNOR; Q96J02; -. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 83737; 18 hits in 1208 CRISPR screens. DR ChiTaRS; ITCH; human. DR EvolutionaryTrace; Q96J02; -. DR GenomeRNAi; 83737; -. DR Pharos; Q96J02; Tbio. DR PRO; PR:Q96J02; -. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; Q96J02; Protein. DR Bgee; ENSG00000078747; Expressed in sperm and 188 other cell types or tissues. DR ExpressionAtlas; Q96J02; baseline and differential. DR GO; GO:0005938; C:cell cortex; IEA:Ensembl. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:ARUK-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IC:UniProt. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:1990763; F:arrestin family protein binding; IPI:UniProtKB. DR GO; GO:0045236; F:CXCR chemokine receptor binding; IPI:UniProtKB. DR GO; GO:0016874; F:ligase activity; IEA:Ensembl. DR GO; GO:0043021; F:ribonucleoprotein complex binding; IPI:UniProtKB. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0044389; F:ubiquitin-like protein ligase binding; IPI:UniProtKB. DR GO; GO:0019787; F:ubiquitin-like protein transferase activity; TAS:Reactome. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0035739; P:CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl. DR GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW. DR GO; GO:0006954; P:inflammatory response; NAS:UniProtKB. DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:2000562; P:negative regulation of CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl. DR GO; GO:0039532; P:negative regulation of cytoplasmic pattern recognition receptor signaling pathway; IDA:UniProt. DR GO; GO:0050687; P:negative regulation of defense response to virus; IMP:UniProtKB. DR GO; GO:0046329; P:negative regulation of JNK cascade; ISS:BHF-UCL. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:BHF-UCL. DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome. DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IEA:Ensembl. DR GO; GO:2000646; P:positive regulation of receptor catabolic process; IMP:UniProtKB. DR GO; GO:0002669; P:positive regulation of T cell anergy; IEA:Ensembl. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:ARUK-UCL. DR GO; GO:0051865; P:protein autoubiquitination; IMP:UniProtKB. DR GO; GO:0035519; P:protein K29-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB. DR GO; GO:0031623; P:receptor internalization; IMP:UniProt. DR GO; GO:0001558; P:regulation of cell growth; NAS:UniProtKB. DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; TAS:Reactome. DR GO; GO:0060544; P:regulation of necroptotic process; TAS:Reactome. DR GO; GO:0090085; P:regulation of protein deubiquitination; ISS:BHF-UCL. DR GO; GO:0002870; P:T cell anergy; IEA:Ensembl. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:MGI. DR GO; GO:0046718; P:viral entry into host cell; TAS:UniProtKB. DR CDD; cd04021; C2_E3_ubiquitin_ligase; 1. DR CDD; cd00078; HECTc; 1. DR CDD; cd00201; WW; 4. DR Gene3D; 2.20.70.10; -; 3. DR Gene3D; 2.60.40.150; C2 domain; 1. DR Gene3D; 3.30.2160.10; Hect, E3 ligase catalytic domain; 1. DR Gene3D; 3.30.2410.10; Hect, E3 ligase catalytic domain; 1. DR Gene3D; 3.90.1750.10; Hect, E3 ligase catalytic domains; 1. DR IDEAL; IID00178; -. 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 PANTHER; PTHR11254:SF66; E3 UBIQUITIN-PROTEIN LIGASE ITCHY HOMOLOG; 1. DR PANTHER; PTHR11254; HECT DOMAIN UBIQUITIN-PROTEIN LIGASE; 1. 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; C2 domain (Calcium/lipid-binding domain, CaLB); 1. DR SUPFAM; SSF56204; Hect, E3 ligase catalytic domain; 1. DR SUPFAM; SSF51045; WW domain; 4. DR PROSITE; PS50004; C2; 1. DR PROSITE; PS50237; HECT; 1. DR PROSITE; PS01159; WW_DOMAIN_1; 4. DR PROSITE; PS50020; WW_DOMAIN_2; 4. DR Genevisible; Q96J02; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Antiviral defense; KW Apoptosis; Cell membrane; Cytoplasm; Direct protein sequencing; Endosome; KW Host-virus interaction; Immunity; Innate immunity; Membrane; Nucleus; KW Phosphoprotein; Reference proteome; Repeat; Transferase; Ubl conjugation; KW Ubl conjugation pathway. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19413330" FT CHAIN 2..903 FT /note="E3 ubiquitin-protein ligase Itchy homolog" FT /id="PRO_0000120317" FT DOMAIN 1..115 FT /note="C2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041" FT DOMAIN 326..359 FT /note="WW 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 358..391 FT /note="WW 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 438..471 FT /note="WW 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 478..511 FT /note="WW 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT DOMAIN 569..903 FT /note="HECT" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104" FT REGION 197..301 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 395..471 FT /note="Required for interaction with FYN" FT /evidence="ECO:0000269|PubMed:16387660" FT REGION 574..583 FT /note="MAP kinase docking site" FT /evidence="ECO:0000250" FT COMPBIAS 206..230 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 233..247 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 252..268 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 269..301 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 871 FT /note="Glycyl thioester intermediate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104" FT MOD_RES 2 FT /note="N-acetylserine" FT /evidence="ECO:0007744|PubMed:19413330" FT MOD_RES 240 FT /note="Phosphoserine; by MAPK8" FT /evidence="ECO:0000250|UniProtKB:Q8C863" FT MOD_RES 263 FT /note="Phosphothreonine; by MAPK8" FT /evidence="ECO:0000250|UniProtKB:Q8C863" FT MOD_RES 273 FT /note="Phosphoserine; by MAPK8" FT /evidence="ECO:0000250|UniProtKB:Q8C863" FT MOD_RES 385 FT /note="Phosphothreonine; by SGK3" FT /evidence="ECO:0000269|PubMed:16888620" FT MOD_RES 420 FT /note="Phosphotyrosine; by FYN" FT /evidence="ECO:0000269|PubMed:16387660" FT MOD_RES 450 FT /note="Phosphoserine; by SGK3" FT /evidence="ECO:0000269|PubMed:16888620" FT VAR_SEQ 1..110 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044732" FT VAR_SEQ 159..200 FT /note="NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTG -> S (in FT isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:11318614, FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:9647693, ECO:0000303|Ref.2" FT /id="VSP_008451" FT MUTAGEN 343 FT /note="Y->F: No effect on phosphorylation on T-cell FT stimulation nor in the presence of FYN." FT /evidence="ECO:0000269|PubMed:16387660" FT MUTAGEN 420 FT /note="Y->F: Greatly reduced phosphorylation on T-cell FT stimulation and in the presence of FYN. Increased FT ITCH-mediated Ub conjugation and degradation of JUNB." FT /evidence="ECO:0000269|PubMed:16387660" FT MUTAGEN 455 FT /note="Y->F: No effect on phosphorylation on T-cell FT stimulation nor in the presence of FYN." FT /evidence="ECO:0000269|PubMed:16387660" FT MUTAGEN 871 FT /note="C->A: Loss of ubiquitin protein ligase activity. FT Results in altered endosomal sorting and reduced FT degradation of CXCR4. Unable to inhibit MAVS-induced FT activation of INFB." FT /evidence="ECO:0000269|PubMed:11046148, FT ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:19881509, FT ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097" FT CONFLICT 297 FT /note="T -> I (in Ref. 3; BAG64996)" FT /evidence="ECO:0000305" FT STRAND 18..29 FT /evidence="ECO:0007829|PDB:2NQ3" FT STRAND 41..47 FT /evidence="ECO:0007829|PDB:2NQ3" FT STRAND 50..53 FT /evidence="ECO:0007829|PDB:2NQ3" FT STRAND 64..73 FT /evidence="ECO:0007829|PDB:2NQ3" FT STRAND 78..85 FT /evidence="ECO:0007829|PDB:2NQ3" FT STRAND 88..90 FT /evidence="ECO:0007829|PDB:2NQ3" FT STRAND 93..101 FT /evidence="ECO:0007829|PDB:2NQ3" FT HELIX 102..108 FT /evidence="ECO:0007829|PDB:2NQ3" FT TURN 109..111 FT /evidence="ECO:0007829|PDB:2NQ3" FT STRAND 112..126 FT /evidence="ECO:0007829|PDB:2NQ3" FT STRAND 130..143 FT /evidence="ECO:0007829|PDB:2NQ3" FT STRAND 332..336 FT /evidence="ECO:0007829|PDB:2DMV" FT STRAND 342..346 FT /evidence="ECO:0007829|PDB:2DMV" FT TURN 347..349 FT /evidence="ECO:0007829|PDB:2DMV" FT STRAND 352..355 FT /evidence="ECO:0007829|PDB:2DMV" FT STRAND 365..368 FT /evidence="ECO:0007829|PDB:2KYK" FT STRAND 374..377 FT /evidence="ECO:0007829|PDB:2KYK" FT STRAND 379..381 FT /evidence="ECO:0007829|PDB:2KYK" FT STRAND 444..448 FT /evidence="ECO:0007829|PDB:5CQ2" FT STRAND 454..458 FT /evidence="ECO:0007829|PDB:5CQ2" FT TURN 459..462 FT /evidence="ECO:0007829|PDB:5CQ2" FT STRAND 463..467 FT /evidence="ECO:0007829|PDB:5CQ2" FT HELIX 469..471 FT /evidence="ECO:0007829|PDB:5DWS" FT STRAND 484..488 FT /evidence="ECO:0007829|PDB:5CQ2" FT STRAND 494..498 FT /evidence="ECO:0007829|PDB:5CQ2" FT TURN 499..502 FT /evidence="ECO:0007829|PDB:5CQ2" FT STRAND 503..507 FT /evidence="ECO:0007829|PDB:5CQ2" FT TURN 509..511 FT /evidence="ECO:0007829|PDB:5CQ2" FT HELIX 528..539 FT /evidence="ECO:0007829|PDB:3TUG" FT TURN 540..542 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 545..551 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 554..556 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 557..567 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 572..574 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 575..580 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 589..603 FT /evidence="ECO:0007829|PDB:3TUG" FT TURN 607..609 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 611..614 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 621..624 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 626..630 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 634..650 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 661..667 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 675..677 FT /evidence="ECO:0007829|PDB:3TUG" FT TURN 678..680 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 682..692 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 696..699 FT /evidence="ECO:0007829|PDB:5C7M" FT STRAND 704..709 FT /evidence="ECO:0007829|PDB:5C7M" FT STRAND 716..721 FT /evidence="ECO:0007829|PDB:5C7M" FT HELIX 724..726 FT /evidence="ECO:0007829|PDB:5C7M" FT TURN 731..733 FT /evidence="ECO:0007829|PDB:5C7M" FT HELIX 735..747 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 751..764 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 767..770 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 775..783 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 790..795 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 798..801 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 807..818 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 821..832 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 842..844 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 848..851 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 855..858 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 867..869 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 870..872 FT /evidence="ECO:0007829|PDB:3TUG" FT STRAND 874..877 FT /evidence="ECO:0007829|PDB:3TUG" FT HELIX 883..895 FT /evidence="ECO:0007829|PDB:3TUG" SQ SEQUENCE 903 AA; 102803 MW; 6777A2043C7B67BC CRC64; MSDSGSQLGS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT NSPKWKQPLT VIVTPVSKLH FRVWSHQTLK SDVLLGTAAL DIYETLKSNN MKLEEVVVTL QLGGDKEPTE TIGDLSICLD GLQLESEVVT NGETTCSENG VSLCLPRLEC NSAISAHCNL CLPGLSDSPI SASRVAGFTG ASQNDDGSRS KDETRVSTNG SDDPEDAGAG ENRRVSGNNS PSLSNGGFKP SRPPRPSRPP PPTPRRPASV NGSPSATSES DGSSTGSLPP TNTNTNTSEG ATSGLIIPLT ISGGSGPRPL NPVTQAPLPP GWEQRVDQHG RVYYVDHVEK RTTWDRPEPL PPGWERRVDN MGRIYYVDHF TRTTTWQRPT LESVRNYEQW QLQRSQLQGA MQQFNQRFIY GNQDLFATSQ SKEFDPLGPL PPGWEKRTDS NGRVYFVNHN TRITQWEDPR SQGQLNEKPL PEGWEMRFTV DGIPYFVDHN RRTTTYIDPR TGKSALDNGP QIAYVRDFKA KVQYFRFWCQ QLAMPQHIKI TVTRKTLFED SFQQIMSFSP QDLRRRLWVI FPGEEGLDYG GVAREWFFLL SHEVLNPMYC LFEYAGKDNY CLQINPASYI NPDHLKYFRF IGRFIAMALF HGKFIDTGFS LPFYKRILNK PVGLKDLESI DPEFYNSLIW VKENNIEECD LEMYFSVDKE ILGEIKSHDL KPNGGNILVT EENKEEYIRM VAEWRLSRGV EEQTQAFFEG FNEILPQQYL QYFDAKELEV LLCGMQEIDL NDWQRHAIYR HYARTSKQIM WFWQFVKEID NEKRMRLLQF VTGTCRLPVG GFADLMGSNG PQKFCIEKVG KENWLPRSHT CFNRLDLPPY KSYEQLKEKL LFAIEETEGF GQE //