XIAP_RAT
ID XIAP_RAT Reviewed; 496 AA.
AC Q9R0I6;
DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=E3 ubiquitin-protein ligase XIAP;
DE EC=2.3.2.27;
DE AltName: Full=Baculoviral IAP repeat-containing protein 4;
DE AltName: Full=IAP homolog A;
DE AltName: Full=Inhibitor of apoptosis protein 3;
DE Short=IAP-3;
DE Short=rIAP-3;
DE Short=rIAP3;
DE AltName: Full=RING-type E3 ubiquitin transferase XIAP;
DE AltName: Full=X-linked inhibitor of apoptosis protein;
DE Short=X-linked IAP;
GN Name=Xiap; Synonyms=Api3, Birc4;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Saito N.;
RT "Rattus norvegicus X-linked inhibitor of apoptosis (riap3) mRNA.";
RL Submitted (OCT-1999) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Multi-functional protein which regulates not only caspases
CC and apoptosis, but also modulates inflammatory signaling and immunity,
CC copper homeostasis, mitogenic kinase signaling, cell proliferation, as
CC well as cell invasion and metastasis. Acts as a direct caspase
CC inhibitor. Directly bind to the active site pocket of CASP3 and CASP7
CC and obstructs substrate entry. Inactivates CASP9 by keeping it in a
CC monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase
CC regulating NF-kappa-B signaling and the target proteins for its E3
CC ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8,
CC CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin.
CC Ubiquitinion of CCS leads to enhancement of its chaperone activity
CC toward its physiologic target, SOD1, rather than proteasomal
CC degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to
CC proteasomal degradation. Plays a role in copper homeostasis by
CC ubiquitinating COMMD1 and promoting its proteasomal degradation. Can
CC also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation
CC pathway, targeting effector caspases for neddylation and inactivation.
CC Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1
CC dependent pathways leading to NF-kappa-B and JNK activation. Acts as an
CC important regulator of innate immune signaling via regulation of
CC Nodlike receptors (NLRs). Protects cells from spontaneous formation of
CC the ripoptosome, a large multi-protein complex that has the capability
CC to kill cancer cells in a caspase-dependent and caspase-independent
CC manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and
CC CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates
CC TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in
CC inhibition of its interaction with TCF7L2/TCF4 thereby allowing
CC efficient recruitment and binding of the transcriptional coactivator
CC beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific
CC transcriptional program (By similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27;
CC -!- SUBUNIT: Monomer, and homodimer. Interacts (via BIR3 domain) with
CC DIABLO/SMAC; the interaction inhibits apoptotic suppressor activity (By
CC similarity). Interacts with HTRA2/PRSS25; the interaction inhibits
CC apoptotic suppressor activity. Interacts with TAB1/MAP3K7IP1 and AIFM1.
CC Interaction with DIABLO/SMAC hinders binding of TAB1/MAP3K7IP1 and
CC AIFM1. Interacts with TCF25 and COMMD1. Interacts (via BIR3 domain)
CC with SEPTIN4 (By similarity). Interacts with RIP1, RIP2, RIP3, RIP4,
CC CCS and USP19. Interacts (via BIR 2 domain and BIR 3 domain) with HAX1
CC (via C-terminus) and this interaction blocks ubiquitination of
CC XIAP/BIRC4. Interacts with the monomeric form of BIRC5/survivin (By
CC similarity). Interacts with TLE3 and TCF7L2/TCF4 (By similarity).
CC Interacts (via BIR 3 and RING domains) with PDCL3 (By similarity).
CC {ECO:0000250, ECO:0000250|UniProtKB:P98170,
CC ECO:0000250|UniProtKB:Q60989}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC Note=TLE3 promotes its nuclear localization. {ECO:0000250}.
CC -!- DOMAIN: The first BIR domain is involved in interaction with
CC TAB1/MAP3K7IP1 and is important for dimerization. The second BIR domain
CC is sufficient to inhibit caspase-3 and caspase-7, while the third BIR
CC is involved in caspase-9 inhibition. The interactions with DIABLO/SMAC
CC and HTRA2/PRSS25 are mediated by the second and third BIR domains (By
CC similarity). {ECO:0000250}.
CC -!- PTM: S-Nitrosylation down-regulates its E3 ubiquitin-protein ligase
CC activity. {ECO:0000250|UniProtKB:P98170}.
CC -!- PTM: Autoubiquitinated. {ECO:0000250|UniProtKB:P98170}.
CC -!- SIMILARITY: Belongs to the IAP family. {ECO:0000305}.
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DR EMBL; AB033366; BAA85304.1; -; mRNA.
DR RefSeq; NP_071567.1; NM_022231.2.
DR RefSeq; XP_006257570.1; XM_006257508.3.
DR RefSeq; XP_006257571.1; XM_006257509.3.
DR RefSeq; XP_017457637.1; XM_017602148.1.
DR RefSeq; XP_017457638.1; XM_017602149.1.
DR RefSeq; XP_017457639.1; XM_017602150.1.
DR RefSeq; XP_017457640.1; XM_017602151.1.
DR AlphaFoldDB; Q9R0I6; -.
DR SMR; Q9R0I6; -.
DR BioGRID; 248914; 5.
DR MINT; Q9R0I6; -.
DR STRING; 10116.ENSRNOP00000009336; -.
DR MEROPS; I32.004; -.
DR MEROPS; I32.007; -.
DR iPTMnet; Q9R0I6; -.
DR PhosphoSitePlus; Q9R0I6; -.
DR PaxDb; Q9R0I6; -.
DR Ensembl; ENSRNOT00000009336; ENSRNOP00000009336; ENSRNOG00000006967.
DR GeneID; 63879; -.
DR KEGG; rno:63879; -.
DR UCSC; RGD:620692; rat.
DR CTD; 331; -.
DR RGD; 620692; Xiap.
DR eggNOG; KOG1101; Eukaryota.
DR GeneTree; ENSGT00940000158743; -.
DR HOGENOM; CLU_016347_1_1_1; -.
DR InParanoid; Q9R0I6; -.
DR OrthoDB; 1340284at2759; -.
DR PhylomeDB; Q9R0I6; -.
DR Reactome; R-RNO-111459; Activation of caspases through apoptosome-mediated cleavage.
DR Reactome; R-RNO-111463; SMAC (DIABLO) binds to IAPs.
DR Reactome; R-RNO-111464; SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes.
DR Reactome; R-RNO-111469; SMAC, XIAP-regulated apoptotic response.
DR Reactome; R-RNO-3769402; Deactivation of the beta-catenin transactivating complex.
DR Reactome; R-RNO-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-RNO-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-RNO-5668541; TNFR2 non-canonical NF-kB pathway.
DR Reactome; R-RNO-5675482; Regulation of necroptotic cell death.
DR Reactome; R-RNO-5676594; TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway.
DR Reactome; R-RNO-8948747; Regulation of PTEN localization.
DR Reactome; R-RNO-8948751; Regulation of PTEN stability and activity.
DR Reactome; R-RNO-9627069; Regulation of the apoptosome activity.
DR PRO; PR:Q9R0I6; -.
DR Proteomes; UP000002494; Chromosome X.
DR Bgee; ENSRNOG00000006967; Expressed in duodenum and 19 other tissues.
DR ExpressionAtlas; Q9R0I6; baseline and differential.
DR Genevisible; Q9R0I6; RN.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:RGD.
DR GO; GO:0032991; C:protein-containing complex; IDA:RGD.
DR GO; GO:0005876; C:spindle microtubule; IBA:GO_Central.
DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0002020; F:protease binding; IPI:RGD.
DR GO; GO:0120283; F:protein serine/threonine kinase binding; ISO:RGD.
DR GO; GO:0097110; F:scaffold protein binding; IPI:RGD.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISO:RGD.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISO:RGD.
DR GO; GO:0097340; P:inhibition of cysteine-type endopeptidase activity; ISO:RGD.
DR GO; GO:1990001; P:inhibition of cysteine-type endopeptidase activity involved in apoptotic process; ISO:RGD.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:RGD.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:RGD.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:RGD.
DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; ISO:RGD.
DR GO; GO:0051402; P:neuron apoptotic process; ISO:RGD.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; ISO:RGD.
DR GO; GO:0046330; P:positive regulation of JNK cascade; ISO:RGD.
DR GO; GO:1902530; P:positive regulation of protein linear polyubiquitination; ISO:RGD.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISO:RGD.
DR GO; GO:0060785; P:regulation of apoptosis involved in tissue homeostasis; ISO:RGD.
DR GO; GO:0042981; P:regulation of apoptotic process; ISO:RGD.
DR GO; GO:0051726; P:regulation of cell cycle; IBA:GO_Central.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR CDD; cd00022; BIR; 3.
DR CDD; cd14395; UBA_BIRC4_8; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR001370; BIR_rpt.
DR InterPro; IPR042579; XIAP/BIRC8_UBA.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR Pfam; PF00653; BIR; 3.
DR SMART; SM00238; BIR; 3.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS01282; BIR_REPEAT_1; 3.
DR PROSITE; PS50143; BIR_REPEAT_2; 3.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 2: Evidence at transcript level;
KW Apoptosis; Cytoplasm; Isopeptide bond; Metal-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat; S-nitrosylation; Transferase;
KW Ubl conjugation; Ubl conjugation pathway; Wnt signaling pathway; Zinc;
KW Zinc-finger.
FT CHAIN 1..496
FT /note="E3 ubiquitin-protein ligase XIAP"
FT /id="PRO_0000122354"
FT REPEAT 26..93
FT /note="BIR 1"
FT REPEAT 163..230
FT /note="BIR 2"
FT REPEAT 264..329
FT /note="BIR 3"
FT ZN_FING 449..484
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT BINDING 299
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00029"
FT BINDING 302
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00029"
FT BINDING 319
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00029"
FT BINDING 326
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00029"
FT MOD_RES 449
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:P98170"
FT CROSSLNK 321
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P98170"
FT CROSSLNK 327
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P98170"
SQ SEQUENCE 496 AA; 56073 MW; E250E3C77461A469 CRC64;
MTFNSFEGSR TVVPADTNKD EEFVEEFNRL KTFANFPSSS PVSASTLARA GFLYTGEGDT
VQCFSCHAAV DRWQYGDSAV GRHRRISPNC RFINGFYFEN GATQSTSPGI QNGQYKSENC
VGNRNHFALD RPSETHADYL LRTGQVVDIS DTIYPRNPAM CSEEARLKTF QNWPDYAHLS
PRELASAGLY YTGIDDQVQC FCCGGKLKNW EPCDRAWSEH RRHFPNCFFV LGRNVNVRSE
SGVSSDRNFP NSTNSPRNPA MAEYDARIVT FGTWLYSVNK EQLARAGFYA LGEGDKVKCF
HCGGGLTDWK PSEDPWEQHA KWYPGCKYLL DEKGQEYINN IHLTHSLGES VVRTAEKTPS
VTKKIDDTIF QNPMVQEAIR MGFNFKDIKK TMEEKLQTSG SNYLSLEVLI ADLVSAQKDN
SQDESSQTSL QKDISTEEQL RRLQEEKLCK ICMDRNIAIV FVPCGHLVTC KQCAEAVDKC
PMCCTVITFK QKIFMS
