CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-004984
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 Tumor necrosis factor alpha-induced protein 3 
Protein Synonyms/Alias
 TNF alpha-induced protein 3; OTU domain-containing protein 7C; Putative DNA-binding protein A20; Zinc finger protein A20; A20p50; A20p37 
Gene Name
 TNFAIP3 
Gene Synonyms/Alias
 OTUD7C 
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
66QFREIIHKALIDRNIubiquitination[1]
81QATLESQKKLNWCREubiquitination[1, 2, 3]
131KALFSTLKETDTRNFubiquitination[1]
301PENEMKEKLLKEYLMubiquitination[1]
354ELVQHEYKKWQENSEubiquitination[4]
355LVQHEYKKWQENSEQubiquitination[1]
424KLPKLNSKPGPEGLPubiquitination[1, 3]
520TRHLDPGKCQACLQDubiquitination[1, 2, 5]
541GICSTCFKRTTAEASubiquitination[1, 2, 5]
643HFAAASGKVSPTASRubiquitination[1, 3, 4, 5]
676MFEGYCQKCFIEAQNubiquitination[1]
715TQSTSRPKCARASCKubiquitination[2]
722KCARASCKNILACRSubiquitination[1, 2, 3, 5, 6, 7]
Reference
 [1] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [2] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [3] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [4] Global identification of modular cullin-RING ligase substrates.
 Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, Yen HC, Elledge SJ.
 Cell. 2011 Oct 14;147(2):459-74. [PMID: 21963094]
 [5] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [6] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [7] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789] 
Functional Description
 Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities. Involved in immune and inflammatory responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B activity. Essential component of a ubiquitin-editing protein complex, comprising also RNF11, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. In cooperation with TAX1BP1 promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, 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 NF-kappa-B. Deubiquinates TRAF6 probably acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor (TCR)-mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin chains on MALT1 thereby mediating disassociation of the CBM (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK activation. Deubiquinates NEMO/IKBKG; the function is facilitated by TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism which involves polyubiquitin; polyubiquitin promotes association with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able to deubiquitinate both 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system. Required for LPS-induced production of proinflammatory cytokines and IFN beta in LPS-tolerized macrophages. 
Sequence Annotation
 DOMAIN 92 263 OTU.
 REPEAT 286 317 1.
 REPEAT 324 356 2.
 ZN_FING 381 416 A20-type 1.
 ZN_FING 472 507 A20-type 2.
 ZN_FING 515 548 A20-type 3.
 ZN_FING 601 636 A20-type 4.
 ZN_FING 651 686 A20-type 5.
 ZN_FING 710 745 A20-type 6.
 ZN_FING 756 790 A20-type 7.
 REGION 58 300 TRAF-binding.
 REGION 157 159 Interaction with ubiquitin (Probable).
 REGION 190 192 Interaction with ubiquitin (Probable).
 REGION 224 227 Interaction with ubiquitin (Probable).
 REGION 286 356 2 X approximate repeats.
 REGION 369 775 Interaction with TNIP1 (By similarity).
 REGION 386 453 Interaction with RIPK1.
 REGION 605 655 Required for proteosomal degradation of
 REGION 606 790 Sufficient for inhibitory activity of
 REGION 697 790 Required for lysosomal localization and
 ACT_SITE 103 103 Nucleophile.
 ACT_SITE 256 256 Proton acceptor (Probable).
 MOD_RES 459 459 Phosphoserine.  
Keyword
 3D-structure; Apoptosis; Complete proteome; Cytoplasm; DNA-binding; Hydrolase; Inflammatory response; Ligase; Lysosome; Metal-binding; Multifunctional enzyme; Nucleus; Phosphoprotein; Polymorphism; Protease; Reference proteome; Repeat; Thiol protease; Ubl conjugation pathway; Zinc; Zinc-finger. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 790 AA 
Protein Sequence
MAEQVLPQAL YLSNMRKAVK IRERTPEDIF KPTNGIIHHF KTMHRYTLEM FRTCQFCPQF 60
REIIHKALID RNIQATLESQ KKLNWCREVR KLVALKTNGD GNCLMHATSQ YMWGVQDTDL 120
VLRKALFSTL KETDTRNFKF RWQLESLKSQ EFVETGLCYD TRNWNDEWDN LIKMASTDTP 180
MARSGLQYNS LEEIHIFVLC NILRRPIIVI SDKMLRSLES GSNFAPLKVG GIYLPLHWPA 240
QECYRYPIVL GYDSHHFVPL VTLKDSGPEI RAVPLVNRDR GRFEDLKVHF LTDPENEMKE 300
KLLKEYLMVI EIPVQGWDHG TTHLINAAKL DEANLPKEIN LVDDYFELVQ HEYKKWQENS 360
EQGRREGHAQ NPMEPSVPQL SLMDVKCETP NCPFFMSVNT QPLCHECSER RQKNQNKLPK 420
LNSKPGPEGL PGMALGASRG EAYEPLAWNP EESTGGPHSA PPTAPSPFLF SETTAMKCRS 480
PGCPFTLNVQ HNGFCERCHN ARQLHASHAP DHTRHLDPGK CQACLQDVTR TFNGICSTCF 540
KRTTAEASSS LSTSLPPSCH QRSKSDPSRL VRSPSPHSCH RAGNDAPAGC LSQAARTPGD 600
RTGTSKCRKA GCVYFGTPEN KGFCTLCFIE YRENKHFAAA SGKVSPTASR FQNTIPCLGR 660
ECGTLGSTMF EGYCQKCFIE AQNQRFHEAK RTEEQLRSSQ RRDVPRTTQS TSRPKCARAS 720
CKNILACRSE ELCMECQHPN QRMGPGAHRG EPAPEDPPKQ RCRAPACDHF GNAKCNGYCN 780
ECFQFKQMYG 790 
Gene Ontology
 GO:0005813; C:centrosome; IDA:HPA.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
 GO:0005634; C:nucleus; IDA:HGNC.
 GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; NAS:BHF-UCL.
 GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
 GO:0043621; F:protein self-association; IDA:BHF-UCL.
 GO:0004221; F:ubiquitin thiolesterase activity; IMP:UniProtKB.
 GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
 GO:0004843; F:ubiquitin-specific protease activity; IDA:UniProtKB.
 GO:0008270; F:zinc ion binding; IEA:InterPro.
 GO:0001922; P:B-1 B cell homeostasis; ISS:BHF-UCL.
 GO:0070301; P:cellular response to hydrogen peroxide; ISS:UniProtKB.
 GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0050869; P:negative regulation of B cell activation; ISS:BHF-UCL.
 GO:0045779; P:negative regulation of bone resorption; NAS:BHF-UCL.
 GO:2000349; P:negative regulation of CD40 signaling pathway; IMP:BHF-UCL.
 GO:0002677; P:negative regulation of chronic inflammatory response; IEA:Compara.
 GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IEA:Compara.
 GO:2000352; P:negative regulation of endothelial cell apoptotic process; IDA:BHF-UCL.
 GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB cascade; IDA:UniProtKB.
 GO:0050728; P:negative regulation of inflammatory response; ISS:BHF-UCL.
 GO:0045824; P:negative regulation of innate immune response; ISS:UniProtKB.
 GO:0032691; P:negative regulation of interleukin-1 beta production; IEA:Compara.
 GO:0032703; P:negative regulation of interleukin-2 production; IMP:BHF-UCL.
 GO:0032715; P:negative regulation of interleukin-6 production; ISS:BHF-UCL.
 GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL.
 GO:0070429; P:negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Compara.
 GO:0070433; P:negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Compara.
 GO:0090291; P:negative regulation of osteoclast proliferation; NAS:BHF-UCL.
 GO:0031397; P:negative regulation of protein ubiquitination; IDA:BHF-UCL.
 GO:0048662; P:negative regulation of smooth muscle cell proliferation; IDA:BHF-UCL.
 GO:0034136; P:negative regulation of toll-like receptor 2 signaling pathway; NAS:BHF-UCL.
 GO:0034140; P:negative regulation of toll-like receptor 3 signaling pathway; IDA:BHF-UCL.
 GO:0034148; P:negative regulation of toll-like receptor 5 signaling pathway; IEA:Compara.
 GO:0032720; P:negative regulation of tumor necrosis factor production; ISS:BHF-UCL.
 GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
 GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
 GO:2000347; P:positive regulation of hepatocyte proliferation; IEA:Compara.
 GO:0045732; P:positive regulation of protein catabolic process; IDA:BHF-UCL.
 GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB.
 GO:0070536; P:protein K63-linked deubiquitination; IDA:UniProtKB.
 GO:0051259; P:protein oligomerization; NAS:BHF-UCL.
 GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
 GO:0050691; P:regulation of defense response to virus by host; NAS:BHF-UCL.
 GO:0002634; P:regulation of germinal center formation; ISS:BHF-UCL.
 GO:0061043; P:regulation of vascular wound healing; NAS:BHF-UCL.
 GO:0032495; P:response to muramyl dipeptide; IEA:Compara.
 GO:0072573; P:tolerance induction to lipopolysaccharide; IMP:BHF-UCL. 
Interpro
 IPR003323; OTU.
 IPR002653; Znf_A20. 
Pfam
 PF02338; OTU
 PF01754; zf-A20 
SMART
 SM00259; ZnF_A20 
PROSITE
 PS50802; OTU
 PS51036; ZF_A20 
PRINTS