CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-016755
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 E3 ubiquitin-protein ligase Itchy 
Protein Synonyms/Alias
  
Gene Name
 Itch 
Gene Synonyms/Alias
  
Created Date
 July 27, 2013 
Organism
 Mus musculus (Mouse) 
NCBI Taxa ID
 10090 
Lysine Modification
Position
Peptide
Type
References
66NTNSPKWKQPLTVIVubiquitination[1]
192VAASGENKRANGNNSubiquitination[1]
311YYVDHVEKRTTWDRPubiquitination[1]
393LFATSQNKEFDPLGPubiquitination[1, 2]
407PLPPGWEKRTDSNGRubiquitination[1]
439SQGQLNEKPLPEGWEubiquitination[1]
474YIDPRTGKSALDNGPubiquitination[1]
Reference
 [1] Proteomic analyses reveal divergent ubiquitylation site patterns in murine tissues.
 Wagner SA, Beli P, Weinert BT, Schölz C, Kelstrup CD, Young C, Nielsen ML, Olsen JV, Brakebusch C, Choudhary C.
 Mol Cell Proteomics. 2012 Dec;11(12):1578-85. [PMID: 22790023]
 [2] BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs.
 Mathew R, Seiler MP, Scanlon ST, Mao AP, Constantinides MG, Bertozzi-Villa C, Singer JD, Bendelac A.
 Nature. 2012 Nov 22;491(7425):618-21. [PMID: 23086144] 
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 (By similarity). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (By similarity). Regulates the transcriptional activity of several transcription factors involved in immune response. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation. Ubiquitinates SNX9 (By similarity). Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway (By similarity). 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 (By similarity). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (By similarity). 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 (By similarity). 
Sequence Annotation
 DOMAIN 5 99 C2.
 DOMAIN 287 320 WW 1.
 DOMAIN 319 352 WW 2.
 DOMAIN 399 432 WW 3.
 DOMAIN 439 472 WW 4.
 DOMAIN 530 864 HECT.
 REGION 356 432 Required for interaction with FYN (By
 REGION 535 544 MAP kinase docking site.
 ACT_SITE 832 832 Glycyl thioester intermediate (By
 MOD_RES 2 2 N-acetylserine (By similarity).
 MOD_RES 199 199 Phosphoserine; by MAPK8.
 MOD_RES 222 222 Phosphothreonine; by MAPK8.
 MOD_RES 232 232 Phosphoserine; by MAPK8.
 MOD_RES 346 346 Phosphothreonine; by SGK3 (By
 MOD_RES 381 381 Phosphotyrosine; by FYN (By similarity).
 MOD_RES 411 411 Phosphoserine; by SGK3 (By similarity).  
Keyword
 3D-structure; Acetylation; Alternative splicing; Antiviral defense; Apoptosis; Cell membrane; Complete proteome; Cytoplasm; Immunity; Innate immunity; Ligase; Membrane; Nucleus; Phosphoprotein; Reference proteome; Repeat; Ubl conjugation; Ubl conjugation pathway. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 864 AA 
Protein Sequence
MSDSGPQLDS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT 60
NSPKWKQPLT VIVTPTSKLC FRVWSHQTLK SDVLLGTAGL DIYETLKSNN MKLEEVVMTL 120
QLVGDKEPTE TMGDLSVCLD GLQVEAEVVT NGETSCSEST TQNDDGCRTR DDTRVSTNGS 180
EDPEVAASGE NKRANGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSTNSDSD 240
GSSTGSLPPT NTNVNTSTSE GATSGLIIPL TISGGSGPRP LNTVSQAPLP PGWEQRVDQH 300
GRVYYVDHVE KRTTWDRPEP LPPGWERRVD NMGRIYYVDH FTRTTTWQRP TLESVRNYEQ 360
WQLQRSQLQG AMQQFNQRFI YGNQDLFATS QNKEFDPLGP LPPGWEKRTD SNGRVYFVNH 420
NTRITQWEDP RSQGQLNEKP LPEGWEMRFT VDGIPYFVDH NRRATTYIDP RTGKSALDNG 480
PQIAYVRDFK AKVQYFRFWC QQLAMPQHIK ITVTRKTLFE DSFQQIMSFS PQDLRRRLWV 540
IFPGEEGLDY GGVAREWFFL LSHEVLNPMY CLFEYAGKDN YCLQINPASY INPDHLKYFR 600
FIGRFIAMAL FHGKFIDTGF SLPFYKRILN KPVGLKDLES IDPEFYNSLI WVKENNIEEC 660
GLEMYFSVDK EILGEIKSHD LKPNGGNILV TEENKEEYIR MVAEWRLSRG VEEQTQAFFE 720
GFNEILPQQY LQYFDAKELE VLLCGMQEID LNDWQRHAIY RHYTRTSKQI MWFWQFVKEI 780
DNEKRMRLLQ FVTGTCRLPV GGFADLMGSN GPQKFCIEKV GKENWLPRSH TCFNRLDLPP 840
YKSYEQLKEK LLFAIEETEG FGQE 864 
Gene Ontology
 GO:0005938; C:cell cortex; IDA:MGI.
 GO:0031410; C:cytoplasmic vesicle; IDA:MGI.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0016020; C:membrane; IDA:MGI.
 GO:0005634; C:nucleus; IDA:MGI.
 GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
 GO:0000151; C:ubiquitin ligase complex; ISA:MGI.
 GO:0043021; F:ribonucleoprotein complex binding; IEA:Compara.
 GO:0004842; F:ubiquitin-protein ligase activity; ISS:UniProtKB.
 GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
 GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
 GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
 GO:0046642; P:negative regulation of alpha-beta T cell proliferation; IMP:MGI.
 GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
 GO:0050687; P:negative regulation of defense response to virus; IMP:UniProtKB.
 GO:0046329; P:negative regulation of JNK cascade; IMP:BHF-UCL.
 GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL.
 GO:0045732; P:positive regulation of protein catabolic process; IDA:MGI.
 GO:0002669; P:positive regulation of T cell anergy; IMP:MGI.
 GO:0035519; P:protein K29-linked ubiquitination; ISS:UniProtKB.
 GO:0070936; P:protein K48-linked ubiquitination; ISS:UniProtKB.
 GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
 GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IDA:MGI.
 GO:0090085; P:regulation of protein deubiquitination; IMP:BHF-UCL. 
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