UniProt Accession

 XIAP_HUMAN; P98170; D3DTF2; Q9NQ14 

Genbank Protein ID

 U32974; U45880; AY886519; AL121601; CH471107; CH471107; CH471107; CH471107; BC032729 

Genbank Nucleotide ID

 AAC50518.1; AAC50373.1; AAW62257.1; CAB95312.1; EAX11858.1; EAX11859.1; EAX11860.1; EAX11861.1; AAH32729.1 

Protein Name

 E3 ubiquitin-protein ligase XIAP 

Protein Synonyms/Alias

 Baculoviral IAP repeat-containing protein 4; IAP-like protein; ILP; hILP; Inhibitor of apoptosis protein 3; IAP-3; hIAP-3; hIAP3; X-linked inhibitor of apoptosis protein; X-linked IAP 

Gene Name

 XIAP 

Gene Synonyms/Alias

 API3; BIRC4; IAP3 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
10	FNSFEGSKTCVPADI	ubiquitination	[1, 2, 3, 4]
19	CVPADINKEEEFVEE	ubiquitination	[3]
31	VEEFNRLKTFANFPS	ubiquitination	[1, 2, 3, 4, 5, 6]
116	GIQNGQYKVENYLGS	ubiquitination	[4, 5, 6]
168	YSEEARLKSFQNWPD	ubiquitination	[1, 2, 3, 4, 5, 7, 8]
206	QCFCCGGKLKNWEPC	ubiquitination	[3]
208	FCCGGKLKNWEPCDR	ubiquitination	[3, 8]
297	YALGEGDKVKCFHCG	ubiquitination	[3]
311	GGGLTDWKPSEDPWE	ubiquitination	[3]
322	DPWEQHAKWYPGCKY	ubiquitination	[4, 9]
328	AKWYPGCKYLLEQKG	ubiquitination	[1, 4, 9]
334	CKYLLEQKGQEYINN	ubiquitination	[3]
358	CLVRTTEKTPSLTRR	ubiquitination	[3, 7, 8]
433	SSQTSLQKEISTEEQ	ubiquitination	[5]
448	LRRLQEEKLCKICMD	ubiquitination	[3]
480	QCAEAVDKCPMCYTV	ubiquitination	[3]

Reference

 [1] 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]
 [2] 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]
 [3] 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]
 [4] 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]
 [5] 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]
 [6] 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]
 [7] A data set of human endogenous protein ubiquitination sites.
 Shi Y, Chan DW, Jung SY, Malovannaya A, Wang Y, Qin J.
 Mol Cell Proteomics. 2011 May;10(5):M110.002089. [PMID: 20972266]
 [8] 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]
 [9] Computational identification of ubiquitylation sites from protein sequences.
 Tung CW, Ho SY.
 BMC Bioinformatics. 2008 Jul 15;9:310. [PMID: 18625080] 

Functional Description

 Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta- catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program. 

Sequence Annotation

 REPEAT 26 93 BIR 1.
 REPEAT 163 230 BIR 2.
 REPEAT 265 330 BIR 3.
 ZN_FING 450 485 RING-type.
 REGION 141 149 Interaction with caspase-7.
 METAL 300 300 Zinc (By similarity).
 METAL 303 303 Zinc (By similarity).
 METAL 320 320 Zinc (By similarity).
 METAL 327 327 Zinc (By similarity).
 MOD_RES 87 87 Phosphoserine; by PKB.
 MOD_RES 450 450 S-nitrosocysteine.
 CROSSLNK 322 322 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 328 328 Glycyl lysine isopeptide (Lys-Gly)  

Keyword

 3D-structure; Apoptosis; Complete proteome; Cytoplasm; Isopeptide bond; Ligase; Metal-binding; Nucleus; Phosphoprotein; Polymorphism; Protease inhibitor; Reference proteome; Repeat; S-nitrosylation; Thiol protease inhibitor; Ubl conjugation; Ubl conjugation pathway; Wnt signaling pathway; Zinc; Zinc-finger. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 497 AA 

Protein Sequence

Gene Ontology

 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005634; C:nucleus; IDA:UniProtKB.
 GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; IDA:ProtInc.
 GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
 GO:0008270; F:zinc ion binding; IEA:InterPro.
 GO:0055070; P:copper ion homeostasis; TAS:UniProtKB.
 GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:Reactome.
 GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
 GO:0090263; P:positive regulation of canonical Wnt receptor signaling pathway; IMP:UniProtKB.
 GO:0030510; P:regulation of BMP signaling pathway; TAS:UniProtKB.
 GO:0042127; P:regulation of cell proliferation; TAS:UniProtKB.
 GO:0050727; P:regulation of inflammatory response; TAS:UniProtKB.
 GO:0045088; P:regulation of innate immune response; TAS:UniProtKB.
 GO:0070424; P:regulation of nucleotide-binding oligomerization domain containing signaling pathway; TAS:UniProtKB.
 GO:0006974; P:response to DNA damage stimulus; IEP:UniProtKB.
 GO:0016055; P:Wnt receptor signaling pathway; IEA:UniProtKB-KW. 

Interpro

 IPR001370; BIR.
 IPR001841; Znf_RING. 

Pfam

 PF00653; BIR 

SMART

 SM00238; BIR
 SM00184; RING 

PROSITE

 PS01282; BIR_REPEAT_1
 PS50143; BIR_REPEAT_2
 PS00518; ZF_RING_1
 PS50089; ZF_RING_2 

PRINTS