ID:XIAP_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase XIAP; EC=6.3.2.-; AltName: Full=Baculoviral IAP repeat-containing protein 4; AltName: Full=IAP-like protein; Short=ILP; Short=hILP; AltName: Full=Inhibitor of apoptosis protein 3; Short=IAP-3; Short=hIAP-3; Short=hIAP3; AltName: Full=X-linked inhibitor of apoptosis protein; Short=X-linked IAP; FUNCTION: 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. SUBUNIT: Monomer, and homodimer. Interacts with DIABLO/SMAC and with PRSS25; these interactions inhibit apoptotic suppressor activity. Interacts with TAB1/MAP3K7IP1 and AIFM1. Interaction with SMAC hinders binding of TAB1/MAP3K7IP1 and AIFM1. Interacts with TCF25 and COMMD1. Interacts with SEPT4 isoform 6, but not with other SEPT4 isoforms. Interacts with RIP1, RIP2, RIP3, RIP4, CCS and USP19. Interacts (via BIR 2 domain and BIR 3 domain) with HAX1 (via C-terminus) and this interaction blocks ubiquitination of XIAP/BIRC4. Interacts with the monomeric form of BIRC5/survivin. Interacts with TLE3 and TCF7L2/TCF4. INTERACTION: P55210:CASP7; NbExp=2; IntAct=EBI-517127, EBI-523958; P55211:CASP9; NbExp=5; IntAct=EBI-517127, EBI-516799; Q9NR28:DIABLO; NbExp=7; IntAct=EBI-517127, EBI-517508; O43464:HTRA2; NbExp=10; IntAct=EBI-517127, EBI-517086; Q9JIY5:Htra2 (xeno); NbExp=4; IntAct=EBI-517127, EBI-2365838; P57078:RIPK4; NbExp=2; IntAct=EBI-517127, EBI-4422308; O43236-6:SEPT4; NbExp=4; IntAct=EBI-517127, EBI-4372019; Q8IUQ4:SIAH1; NbExp=3; IntAct=EBI-517127, EBI-747107; P51668:UBE2D1; NbExp=2; IntAct=EBI-517127, EBI-743540; P62837:UBE2D2; NbExp=2; IntAct=EBI-517127, EBI-347677; P61077:UBE2D3; NbExp=2; IntAct=EBI-517127, EBI-348268; P61088:UBE2N; NbExp=2; IntAct=EBI-517127, EBI-1052908; Q13404:UBE2V1; NbExp=2; IntAct=EBI-517127, EBI-1050671; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=TLE3 promotes its nuclear localization. TISSUE SPECIFICITY: Ubiquitous, except peripheral blood leukocytes. DOMAIN: The first BIR domain is involved in interaction with TAB1/MAP3K7IP1 and is important for dimerization. The second BIR domain is sufficient to inhibit CASP3 and CASP7, while the third BIR is involved in CASP9 inhibition. The interactions with DIABLO/SMAC and PRSS25 are mediated by the second and third BIR domains. PTM: S-Nitrosylation down-regulates its E3 ubiquitin-protein ligase activity. PTM: Autoubiquitinated and degraded by the proteasome in apoptotic cells. PTM: Phosphorylation by PKB/AKT protects XIAP against ubiquitination and protects the protein against proteasomal degradation. DISEASE: Defects in XIAP are the cause of lymphoproliferative syndrome X-linked type 2 (XLP2) [MIM:300635]. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma. SIMILARITY: Belongs to the IAP family. SIMILARITY: Contains 3 BIR repeats. SIMILARITY: Contains 1 RING-type zinc finger. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/XIAP"; WEB RESOURCE: Name=BIRC4base; Note=XIAP mutation db; URL="http://bioinf.uta.fi/BIRC4base/"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/birc4/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P98170
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0004842 ubiquitin-protein transferase activity GO:0004869 cysteine-type endopeptidase inhibitor activity GO:0005515 protein binding GO:0016740 transferase activity GO:0030414 peptidase inhibitor activity GO:0042802 identical protein binding GO:0043027 cysteine-type endopeptidase inhibitor activity involved in apoptotic process GO:0046872 metal ion binding GO:0061630 ubiquitin protein ligase activity
Biological Process: GO:0006915 apoptotic process GO:0006974 cellular response to DNA damage stimulus GO:0010466 negative regulation of peptidase activity GO:0016055 Wnt signaling pathway GO:0016567 protein ubiquitination GO:0030510 regulation of BMP signaling pathway GO:0031398 positive regulation of protein ubiquitination GO:0042127 regulation of cell proliferation GO:0043066 negative regulation of apoptotic process GO:0043154 negative regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0045088 regulation of innate immune response GO:0050727 regulation of inflammatory response GO:0055070 copper ion homeostasis GO:0070424 regulation of nucleotide-binding oligomerization domain containing signaling pathway GO:0090263 positive regulation of canonical Wnt signaling pathway GO:1902530 positive regulation of protein linear polyubiquitination GO:1990001 inhibition of cysteine-type endopeptidase activity involved in apoptotic process GO:0090307 mitotic spindle assembly
BC030771 - Homo sapiens baculoviral IAP repeat-containing 4, mRNA (cDNA clone IMAGE:4814521). AK313883 - Homo sapiens cDNA, FLJ94517, highly similar to Homo sapiens baculoviral IAP repeat-containing 4 (BIRC4), mRNA. AK309704 - Homo sapiens cDNA, FLJ99745. HV708937 - JP 2012506450-A/35: Methods for treating eye disorders. U32974 - Human IAP-like protein ILP mRNA, complete cds. BC032729 - Homo sapiens X-linked inhibitor of apoptosis, mRNA (cDNA clone MGC:45369 IMAGE:5532247), complete cds. DD104489 - METHODS FOR IDENTIFYING SMALL MOLECULES THAT BIND SPECIFIC RNA STRUCTURAL MOTIFS. U45880 - Human X-linked inhibitor of apotosis protein XIAP mRNA, complete cds. CU689510 - Synthetic construct Homo sapiens gateway clone IMAGE:100019679 5' read BIRC4 mRNA. AB528456 - Synthetic construct DNA, clone: pF1KB5887, Homo sapiens XIAP gene for X-linked inhibitor of apoptosis, without stop codon, in Flexi system. DQ894012 - Synthetic construct Homo sapiens clone IMAGE:100008472; FLH166540.01L; RZPDo839A0387D baculoviral IAP repeat-containing 4 (BIRC4) gene, encodes complete protein. DQ890857 - Synthetic construct clone IMAGE:100003487; FLH166544.01X; RZPDo839A0388D baculoviral IAP repeat-containing 4 (BIRC4) gene, encodes complete protein. KJ896441 - Synthetic construct Homo sapiens clone ccsbBroadEn_05835 XIAP gene, encodes complete protein. JD055707 - Sequence 36731 from Patent EP1572962. JD224313 - Sequence 205337 from Patent EP1572962. JD442612 - Sequence 423636 from Patent EP1572962. JD349674 - Sequence 330698 from Patent EP1572962. JD482497 - Sequence 463521 from Patent EP1572962. JD337582 - Sequence 318606 from Patent EP1572962. JD371279 - Sequence 352303 from Patent EP1572962. JD542917 - Sequence 523941 from Patent EP1572962. JD213069 - Sequence 194093 from Patent EP1572962. JD024015 - Sequence 5039 from Patent EP1572962. BC046147 - Homo sapiens mRNA similar to SMC (structural maintenance of chromosomes 1)-like 1 (S. cerevisiae) (cDNA clone IMAGE:6064730). AK130423 - Homo sapiens cDNA FLJ26913 fis, clone RCT02969. JD301083 - Sequence 282107 from Patent EP1572962. JD256488 - Sequence 237512 from Patent EP1572962. JD256489 - Sequence 237513 from Patent EP1572962. JD476541 - Sequence 457565 from Patent EP1572962. JD564374 - Sequence 545398 from Patent EP1572962. JD558293 - Sequence 539317 from Patent EP1572962. JD105568 - Sequence 86592 from Patent EP1572962. JD208621 - Sequence 189645 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_caspasePathway - Caspase Cascade in Apoptosis h_bcellsurvivalPathway - B Cell Survival Pathway h_mitochondriaPathway - Role of Mitochondria in Apoptotic Signaling h_HivnefPathway - HIV-I Nef: negative effector of Fas and TNF h_deathPathway - Induction of apoptosis through DR3 and DR4/5 Death Receptors
Reactome (by CSHL, EBI, and GO)
Protein P98170 (Reactome details) participates in the following event(s):
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
