CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-019357
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 E3 ubiquitin-protein ligase Itchy homolog 
Protein Synonyms/Alias
 Itch; Atrophin-1-interacting protein 4; AIP4; NFE2-associated polypeptide 1; NAPP1 
Gene Name
 ITCH 
Gene Synonyms/Alias
  
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
34AKLKENKKNWFGPSPubiquitination[1]
66NTNSPKWKQPLTVIVubiquitination[1]
391LFATSQSKEFDPLGPubiquitination[1]
405PLPPGWEKRTDSNGRubiquitination[1]
437SQGQLNEKPLPEGWEubiquitination[1]
472YIDPRTGKSALDNGPubiquitination[1]
Reference
 [1] Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.
 Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW.
 Nature. 2013 Apr 18;496(7445):372-6. [PMID: 23503661] 
Functional Description
 Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. Is an essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1. Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response. Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation (By similarity). Ubiquitinates SNX9. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway. It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP. Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination. 
Sequence Annotation
 DOMAIN 5 99 C2.
 DOMAIN 326 359 WW 1.
 DOMAIN 358 391 WW 2.
 DOMAIN 438 471 WW 3.
 DOMAIN 478 511 WW 4.
 DOMAIN 569 903 HECT.
 REGION 395 471 Required for interaction with FYN.
 REGION 574 583 MAP kinase docking site (By similarity).
 ACT_SITE 871 871 Glycyl thioester intermediate (By
 MOD_RES 2 2 N-acetylserine.
 MOD_RES 240 240 Phosphoserine; by MAPK8 (By similarity).
 MOD_RES 263 263 Phosphothreonine; by MAPK8 (By
 MOD_RES 273 273 Phosphoserine; by MAPK8 (By similarity).
 MOD_RES 385 385 Phosphothreonine; by SGK3.
 MOD_RES 420 420 Phosphotyrosine; by FYN.
 MOD_RES 450 450 Phosphoserine; by SGK3.  
Keyword
 3D-structure; Acetylation; Alternative splicing; Antiviral defense; Apoptosis; Cell membrane; Complete proteome; Cytoplasm; Direct protein sequencing; Host-virus interaction; Immunity; Innate immunity; Ligase; Membrane; Nucleus; Phosphoprotein; Reference proteome; Repeat; Ubl conjugation; Ubl conjugation pathway. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 903 AA 
Protein Sequence
MSDSGSQLGS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT 60
NSPKWKQPLT VIVTPVSKLH FRVWSHQTLK SDVLLGTAAL DIYETLKSNN MKLEEVVVTL 120
QLGGDKEPTE TIGDLSICLD GLQLESEVVT NGETTCSESA SQNDDGSRSK DETRVSTNGS 180
DDPEDAGAGE NRRVSGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSATSESD 240
GSSTGSLPPT NTNTNTSEGA TSGLIIPLTI SGGSGPRPLN PVTQAPLPPG WEQRVDQHGR 300
VYYVDHVEKR TTWDRPEPLP PGWERRVDNM GRIYYVDHFT RTTTWQRPTL ESVRNYEQWQ 360
LQRSQLQGAM QQFNQRFIYG NQDLFATSQS KEFDPLGPLP PGWEKRTDSN GRVYFVNHNT 420
RITQWEDPRS QGQLNEKPLP EGWEMRFTVD GIPYFVDHNR RTTTYIDPRT GKSALDNGPQ 480
IAYVRDFKAK VQYFRFWCQQ LAMPQHIKIT VTRKTLFEDS FQQIMSFSPQ DLRRRLWVIF 540
PGEEGLDYGG VAREWFFLLS HEVLNPMYCL FEYAGKDNYC LQINPASYIN PDHLKYFRFI 600
GRFIAMALFH GKFIDTGFSL PFYKRILNKP VGLKDLESID PEFYNSLIWV KENNIEECDL 660
EMYFSVDKEI LGEIKSHDLK PNGGNILVTE ENKEEYIRMV AEWRLSRGVE EQTQAFFEGF 720
NEILPQQYLQ YFDAKELEVL LCGMQEIDLN DWQRHAIYRH YARTSKQIMW FWQFVKEIDN 780
EKRMRLLQFV TGTCRLPVGG FADLMGSNGP QKFCIEKVGK ENWLPRSHTC FNRLDLPPYK 840
SYEQLKEKLL FAIEETEGFG QE 862 
Gene Ontology
 GO:0005938; C:cell cortex; IEA:Compara.
 GO:0031410; C:cytoplasmic vesicle; IEA:Compara.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005634; C:nucleus; IBA:RefGenome.
 GO:0005886; C:plasma membrane; IDA:UniProtKB.
 GO:0043021; F:ribonucleoprotein complex binding; IPI:UniProtKB.
 GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
 GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
 GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
 GO:0006954; P:inflammatory response; NAS:UniProtKB.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0046642; P:negative regulation of alpha-beta T cell proliferation; IEA:Compara.
 GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
 GO:0050687; P:negative regulation of defense response to virus; IMP:UniProtKB.
 GO:0046329; P:negative regulation of JNK cascade; ISS:BHF-UCL.
 GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:BHF-UCL.
 GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
 GO:0007219; P:Notch signaling pathway; TAS:Reactome.
 GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
 GO:0045732; P:positive regulation of protein catabolic process; IEA:Compara.
 GO:0002669; P:positive regulation of T cell anergy; IEA:Compara.
 GO:0035519; P:protein K29-linked ubiquitination; IDA:UniProtKB.
 GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB.
 GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
 GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IBA:RefGenome.
 GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
 GO:0090085; P:regulation of protein deubiquitination; ISS:BHF-UCL.
 GO:0046718; P:viral entry into host cell; TAS:UniProtKB. 
Interpro
 IPR000008; C2_Ca-dep.
 IPR008973; C2_Ca/lipid-bd_dom_CaLB.
 IPR018029; C2_membr_targeting.
 IPR024928; E3_ub_ligase_SMURF1.
 IPR000569; HECT.
 IPR001202; WW_dom. 
Pfam
 PF00168; C2
 PF00632; HECT
 PF00397; WW 
SMART
 SM00239; C2
 SM00119; HECTc
 SM00456; WW 
PROSITE
 PS50004; C2
 PS50237; HECT
 PS01159; WW_DOMAIN_1
 PS50020; WW_DOMAIN_2 
PRINTS