P98170 · XIAP_HUMAN
- ProteinE3 ubiquitin-protein ligase XIAP
- GeneXIAP
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids497 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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 (PubMed:11257230, PubMed:11257231, PubMed:11447297, PubMed:12121969, PubMed:12620238, PubMed:17560374, PubMed:17967870, PubMed:19473982, PubMed:20154138, PubMed:22103349, PubMed:9230442).
Acts as a direct caspase inhibitor (PubMed:11257230, PubMed:11257231, PubMed:12620238).
Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry (PubMed:11257230, PubMed:11257231, PubMed:16352606, PubMed:16916640).
Inactivates CASP9 by keeping it in a monomeric, inactive state (PubMed:12620238).
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, RIPK2, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS, PTEN and BIRC5/survivin (PubMed:17560374, PubMed:17967870, PubMed:19473982, PubMed:20154138, PubMed:22103349, PubMed:22607974, PubMed:29452636, PubMed:30026309).
Acts as an important regulator of innate immunity by mediating 'Lys-63'-linked polyubiquitination of RIPK2 downstream of NOD1 and NOD2, thereby transforming RIPK2 into a scaffolding protein for downstream effectors, ultimately leading to activation of the NF-kappa-B and MAP kinases signaling (PubMed:19667203, PubMed:22607974, PubMed:29452636, PubMed:30026309).
'Lys-63'-linked polyubiquitination of RIPK2 also promotes recruitment of the LUBAC complex to RIPK2 (PubMed:22607974, PubMed:29452636).
Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation (PubMed:17560374).
Ubiquitination of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation (PubMed:20154138).
Ubiquitination of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation (PubMed:17967870, PubMed:22103349).
Plays a role in copper homeostasis by ubiquitinating COMMD1 and promoting its proteasomal degradation (PubMed:14685266).
Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation (PubMed:21145488).
Ubiquitinates and therefore mediates the proteasomal degradation of BCL2 in response to apoptosis (PubMed:29020630).
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 (PubMed:22095281).
Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8 (PubMed:22095281).
Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES (PubMed:22304967).
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 (PubMed:22304967).
Acts as a direct caspase inhibitor (PubMed:11257230, PubMed:11257231, PubMed:12620238).
Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry (PubMed:11257230, PubMed:11257231, PubMed:16352606, PubMed:16916640).
Inactivates CASP9 by keeping it in a monomeric, inactive state (PubMed:12620238).
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, RIPK2, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS, PTEN and BIRC5/survivin (PubMed:17560374, PubMed:17967870, PubMed:19473982, PubMed:20154138, PubMed:22103349, PubMed:22607974, PubMed:29452636, PubMed:30026309).
Acts as an important regulator of innate immunity by mediating 'Lys-63'-linked polyubiquitination of RIPK2 downstream of NOD1 and NOD2, thereby transforming RIPK2 into a scaffolding protein for downstream effectors, ultimately leading to activation of the NF-kappa-B and MAP kinases signaling (PubMed:19667203, PubMed:22607974, PubMed:29452636, PubMed:30026309).
'Lys-63'-linked polyubiquitination of RIPK2 also promotes recruitment of the LUBAC complex to RIPK2 (PubMed:22607974, PubMed:29452636).
Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation (PubMed:17560374).
Ubiquitination of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation (PubMed:20154138).
Ubiquitination of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation (PubMed:17967870, PubMed:22103349).
Plays a role in copper homeostasis by ubiquitinating COMMD1 and promoting its proteasomal degradation (PubMed:14685266).
Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation (PubMed:21145488).
Ubiquitinates and therefore mediates the proteasomal degradation of BCL2 in response to apoptosis (PubMed:29020630).
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 (PubMed:22095281).
Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8 (PubMed:22095281).
Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES (PubMed:22304967).
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 (PubMed:22304967).
Catalytic activity
Features
Showing features for binding site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
XIAP is indispensable for NOD2 signaling where it ubiquitylates RIPK2 to recruit LUBAC.
Names & Taxonomy
Protein names
- Recommended nameE3 ubiquitin-protein ligase XIAP
- EC number
- Alternative names
Gene names
- Community suggested namesNOD2; IAP; RIPK2.
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP98170
- Secondary accessions
Proteomes
Organism-specific databases
Disease & Variants
Involvement in disease
Lymphoproliferative syndrome, X-linked, 2 (XLP2)
- Note
- DescriptionA 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.
- See alsoMIM:300635
Natural variants in XLP2
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_088127 | 104-497 | missing | in XLP2; uncertain significance | |
VAR_088128 | 118-497 | missing | in XLP2; uncertain significance | |
VAR_088129 | 188 | G>E | in XLP2; uncertain significance | |
VAR_088130 | 194 | I>N | in XLP2; uncertain significance | |
VAR_088131 | 238-497 | missing | in XLP2; uncertain significance | |
VAR_088132 | 333-497 | missing | in XLP2; uncertain significance | |
VAR_088133 | 381-497 | missing | in XLP2; uncertain significance | |
VAR_088134 | 466-497 | missing | in XLP2; uncertain significance | |
VAR_088135 | 482 | P>R | in XLP2; uncertain significance |
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 75 | Loss of interaction with TAB1/MAP3K7IP1; when associated with G-75. | ||||
Sequence: Y → G | ||||||
Mutagenesis | 80 | Strongly reduced interaction with TAB1/MAP3K7IP1. Reduced activation of MAP3K7/TAK1. Reduced activation of NF-kappa-B. | ||||
Sequence: V → A | ||||||
Mutagenesis | 80 | Loss of interaction with TAB1/MAP3K7IP1. Reduced activation of MAP3K7/TAK1. Strongly reduced activation of NF-kappa-B. | ||||
Sequence: V → D | ||||||
Mutagenesis | 86 | Loss of dimerization. Reduces activation of NF-kappa-B. | ||||
Sequence: V → E | ||||||
Mutagenesis | 87 | No effect on dimerization. | ||||
Sequence: S → A | ||||||
Mutagenesis | 87 | Abolishes dimerization. Interferes with ubiquitination. | ||||
Sequence: S → D or E | ||||||
Mutagenesis | 98 | Loss of interaction with TAB1/MAP3K7IP1; when associated with G-75. | ||||
Sequence: L → G | ||||||
Natural variant | VAR_088127 | 104-497 | in XLP2; uncertain significance | |||
Sequence: Missing | ||||||
Natural variant | VAR_022282 | 107 | in dbSNP:rs28382721 | |||
Sequence: N → S | ||||||
Natural variant | VAR_088128 | 118-497 | in XLP2; uncertain significance | |||
Sequence: Missing | ||||||
Natural variant | VAR_022283 | 133 | in dbSNP:rs28382722 | |||
Sequence: S → F | ||||||
Mutagenesis | 141 | Reduced inhibition of caspase-3. | ||||
Sequence: L → A | ||||||
Mutagenesis | 147 | Reduced inhibition of caspase-3. | ||||
Sequence: V → A | ||||||
Mutagenesis | 148 | Abolishes inhibition of caspase-3. Reduced interaction with HTRA2; when associated with S-214. | ||||
Sequence: D → A | ||||||
Mutagenesis | 149 | Reduced inhibition of caspase-3. | ||||
Sequence: I → A | ||||||
Mutagenesis | 151 | Reduced inhibition of caspase-3. | ||||
Sequence: D → A | ||||||
Mutagenesis | 167 | Reduced inhibition of caspase-3. | ||||
Sequence: L → A | ||||||
Natural variant | VAR_088129 | 188 | in XLP2; uncertain significance | |||
Sequence: G → E | ||||||
Natural variant | VAR_088130 | 194 | in XLP2; uncertain significance | |||
Sequence: I → N | ||||||
Mutagenesis | 196 | Reduced inhibition of caspase-3. May affect protein folding and stability. | ||||
Sequence: D → A | ||||||
Mutagenesis | 214 | Reduced interaction with HTRA2. Reduced interaction with HTRA2; when associated with A-148. | ||||
Sequence: D → S | ||||||
Natural variant | VAR_088131 | 238-497 | in XLP2; uncertain significance | |||
Sequence: Missing | ||||||
Natural variant | VAR_022284 | 242 | in dbSNP:rs28382723 | |||
Sequence: D → E | ||||||
Mutagenesis | 259 | Reduced interaction with HTRA2; when associated with S-314. | ||||
Sequence: N → D | ||||||
Mutagenesis | 310 | No effect on interaction with SEPTIN4 isoform ARTS. | ||||
Sequence: W → A | ||||||
Mutagenesis | 310 | Reduced interaction with HTRA2; when associated with S-314. | ||||
Sequence: W → R | ||||||
Mutagenesis | 314 | Decreased interaction with DIABLO/SMAC and with HTRA2. Decreases interaction with HTRA2; when associated with D-259 or A-310. No effect on interaction with SEPTIN4 isoform ARTS. | ||||
Sequence: E → S | ||||||
Natural variant | VAR_088132 | 333-497 | in XLP2; uncertain significance | |||
Sequence: Missing | ||||||
Mutagenesis | 343 | No effect on interaction with SEPTIN4 isoform ARTS. | ||||
Sequence: H → A | ||||||
Natural variant | VAR_088133 | 381-497 | in XLP2; uncertain significance | |||
Sequence: Missing | ||||||
Natural variant | VAR_022285 | 423 | in dbSNP:rs5956583 | |||
Sequence: Q → P | ||||||
Mutagenesis | 450 | Inhibits degradation of active caspase-3. | ||||
Sequence: C → A or S | ||||||
Natural variant | VAR_088134 | 466-497 | in XLP2; uncertain significance | |||
Sequence: Missing | ||||||
Mutagenesis | 467 | Loss of E3 ubiquitin-protein ligase activity. | ||||
Sequence: H → A | ||||||
Natural variant | VAR_088135 | 482 | in XLP2; uncertain significance | |||
Sequence: P → R | ||||||
Mutagenesis | 495 | Abolished E3 ubiquitin-protein ligase activity and ability to ubiquitinate RIPK2. | ||||
Sequence: F → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 522 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue (large scale data), cross-link, modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000122352 | 1-497 | UniProt | E3 ubiquitin-protein ligase XIAP | |||
Sequence: MTFNSFEGSKTCVPADINKEEEFVEEFNRLKTFANFPSGSPVSASTLARAGFLYTGEGDTVRCFSCHAAVDRWQYGDSAVGRHRKVSPNCRFINGFYLENSATQSTNSGIQNGQYKVENYLGSRDHFALDRPSETHADYLLRTGQVVDISDTIYPRNPAMYSEEARLKSFQNWPDYAHLTPRELASAGLYYTGIGDQVQCFCCGGKLKNWEPCDRAWSEHRRHFPNCFFVLGRNLNIRSESDAVSSDRNFPNSTNLPRNPSMADYEARIFTFGTWIYSVNKEQLARAGFYALGEGDKVKCFHCGGGLTDWKPSEDPWEQHAKWYPGCKYLLEQKGQEYINNIHLTHSLEECLVRTTEKTPSLTRRIDDTIFQNPMVQEAIRMGFSFKDIKKIMEEKIQISGSNYKSLEVLVADLVNAQKDSMQDESSQTSLQKEISTEEQLRRLQEEKLCKICMDRNIAIVFVPCGHLVTCKQCAEAVDKCPMCYTVITFKQKIFMS | |||||||
Modified residue (large scale data) | 5 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 40 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 139 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue (large scale data) | 180 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Cross-link | 322 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Cross-link | 328 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 406 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 450 | UniProt | S-nitrosocysteine | ||||
Sequence: C |
Post-translational modification
S-Nitrosylation down-regulates its E3 ubiquitin-protein ligase activity.
Autoubiquitinated (PubMed:12747801).
Ubiquitinated by TRIM32; leading to proteasomal degradation (PubMed:21628460).
Ubiquitinated by TRIM32; leading to proteasomal degradation (PubMed:21628460).
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Subunit
Monomer, and homodimer. Part of a complex composed of SEPTIN4 isoform ARTS, XIAP and BCL2, within the complex interacts with SEPTIN4 isoform ARTS and BCL2, SEPTIN4 isoform ARTS acts as a scaffold protein and stabilizes the complex (PubMed:29020630).
Interacts (via BIR3 domain) with DIABLO/SMAC; the interaction inhibits apoptotic suppressor activity (PubMed:11140637, PubMed:11257230, PubMed:21695558).
Interacts with HTRA2/PRSS25; the interaction inhibits apoptotic suppressor activity (PubMed:11604410).
Interacts with TAB1/MAP3K7IP1 and AIFM1. Interaction with DIABLO/SMAC hinders binding of TAB1/MAP3K7IP1 and AIFM1. Interacts with TCF25 and COMMD1. Interacts (via BIR3 domain) with SEPTIN4 isoform ARTS (PubMed:15029247, PubMed:21695558).
Interacts (via BIR3 domain) with SEPTIN4 (By similarity).
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. Interacts (via BIR 3 and RING domains) with PDCL3 (PubMed:19012568).
Interacts (via BIR3 domain) with DIABLO/SMAC; the interaction inhibits apoptotic suppressor activity (PubMed:11140637, PubMed:11257230, PubMed:21695558).
Interacts with HTRA2/PRSS25; the interaction inhibits apoptotic suppressor activity (PubMed:11604410).
Interacts with TAB1/MAP3K7IP1 and AIFM1. Interaction with DIABLO/SMAC hinders binding of TAB1/MAP3K7IP1 and AIFM1. Interacts with TCF25 and COMMD1. Interacts (via BIR3 domain) with SEPTIN4 isoform ARTS (PubMed:15029247, PubMed:21695558).
Interacts (via BIR3 domain) with SEPTIN4 (By similarity).
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. Interacts (via BIR 3 and RING domains) with PDCL3 (PubMed:19012568).
Binary interactions
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for repeat, region, zinc finger.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Repeat | 26-93 | BIR 1 | ||||
Sequence: EFNRLKTFANFPSGSPVSASTLARAGFLYTGEGDTVRCFSCHAAVDRWQYGDSAVGRHRKVSPNCRFI | ||||||
Region | 141-149 | Interaction with caspase-7 | ||||
Sequence: LRTGQVVDI | ||||||
Repeat | 163-230 | BIR 2 | ||||
Sequence: EEARLKSFQNWPDYAHLTPRELASAGLYYTGIGDQVQCFCCGGKLKNWEPCDRAWSEHRRHFPNCFFV | ||||||
Region | 262-277 | Required for interaction with SEPTIN4 isoform ARTS | ||||
Sequence: MADYEARIFTFGTWIY | ||||||
Repeat | 265-330 | BIR 3 | ||||
Sequence: YEARIFTFGTWIYSVNKEQLARAGFYALGEGDKVKCFHCGGGLTDWKPSEDPWEQHAKWYPGCKYL | ||||||
Region | 329-350 | Required for interaction with DIABLO | ||||
Sequence: YLLEQKGQEYINNIHLTHSLEE | ||||||
Zinc finger | 450-485 | RING-type | ||||
Sequence: CKICMDRNIAIVFVPCGHLVTCKQCAEAVDKCPMCY | ||||||
Region | 450-497 | Required for ubiquitination and subsequent degradation of BCL2 during apoptosis | ||||
Sequence: CKICMDRNIAIVFVPCGHLVTCKQCAEAVDKCPMCYTVITFKQKIFMS |
Domain
The first BIR domain is involved in interaction with TAB1/MAP3K7IP1 and is important for dimerization (PubMed:17560374).
The second BIR domain is sufficient to inhibit CASP3 and CASP7, while the third BIR is involved in CASP9 inhibition (PubMed:11257231, PubMed:12620238).
The interactions with DIABLO/SMAC and HTRA2/PRSS25 are mediated by the second and third BIR domains
The second BIR domain is sufficient to inhibit CASP3 and CASP7, while the third BIR is involved in CASP9 inhibition (PubMed:11257231, PubMed:12620238).
The interactions with DIABLO/SMAC and HTRA2/PRSS25 are mediated by the second and third BIR domains
Sequence similarities
Belongs to the IAP family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length497
- Mass (Da)56,685
- Last updated2001-01-24 v2
- Checksum9D394C16D45EB635
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 162 | in Ref. 2; AAC50373 | ||||
Sequence: S → C |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
U32974 EMBL· GenBank· DDBJ | AAC50518.1 EMBL· GenBank· DDBJ | mRNA | ||
U45880 EMBL· GenBank· DDBJ | AAC50373.1 EMBL· GenBank· DDBJ | mRNA | ||
AY886519 EMBL· GenBank· DDBJ | AAW62257.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AL121601 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471107 EMBL· GenBank· DDBJ | EAX11858.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471107 EMBL· GenBank· DDBJ | EAX11859.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471107 EMBL· GenBank· DDBJ | EAX11860.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471107 EMBL· GenBank· DDBJ | EAX11861.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC032729 EMBL· GenBank· DDBJ | AAH32729.1 EMBL· GenBank· DDBJ | mRNA |