P98170 (XIAP_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
E3 ubiquitin-protein ligase XIAP
EC=6.3.2.-

Alternative name(s):
Baculoviral IAP repeat-containing protein 4
IAP-like protein
Short name=ILP
Short name=hILP
Inhibitor of apoptosis protein 3
Short name=IAP-3
Short name=hIAP-3
Short name=hIAP3
X-linked inhibitor of apoptosis protein
Short name=X-linked IAP

Gene names

Name:	XIAP
Synonyms:	API3, BIRC4, IAP3

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	497 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

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. Ref.7 Ref.8 Ref.10 Ref.12 Ref.14 Ref.20 Ref.22 Ref.26 Ref.27 Ref.30 Ref.36 Ref.44
Subunit structure	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. Ref.12 Ref.13 Ref.18 Ref.20 Ref.22 Ref.23 Ref.27 Ref.32 Ref.33 Ref.34 Ref.36 Ref.43
Subcellular location	Cytoplasm. Nucleus. Note: TLE3 promotes its nuclear localization. Ref.15 Ref.36
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.
Post-translational modification	S-Nitrosylation down-regulates its E3 ubiquitin-protein ligase activity. Autoubiquitinated and degraded by the proteasome in apoptotic cells. Phosphorylation by PKB/AKT protects XIAP against ubiquitination and protects the protein against proteasomal degradation.
Involvement in disease	Lymphoproliferative syndrome, X-linked, 2 (XLP2) [MIM:300635]: 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.16
Sequence similarities	Belongs to the IAP family. Contains 3 BIR repeats. Contains 1 RING-type zinc finger.

Ontologies

Keywords
Biological process	Apoptosis Ubl conjugation pathway Wnt signaling pathway
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Domain	Repeat Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Ligase Protease inhibitor Thiol protease inhibitor
PTM	Isopeptide bond Phosphoprotein S-nitrosylation Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW copper ion homeostasis Traceable author statement Ref.17. Source: UniProtKB negative regulation of apoptotic process Inferred from mutant phenotype PubMed 18049476PubMed 22173242. Source: UniProtKB positive regulation of canonical Wnt receptor signaling pathway Inferred from mutant phenotype Ref.36. Source: UniProtKB regulation of BMP signaling pathway Traceable author statement Ref.19. Source: UniProtKB regulation of cell proliferation Traceable author statement Ref.19. Source: UniProtKB regulation of inflammatory response Traceable author statement Ref.31. Source: UniProtKB regulation of innate immune response Traceable author statement Ref.31. Source: UniProtKB regulation of nucleotide-binding oligomerization domain containing signaling pathway Traceable author statement Ref.24. Source: UniProtKB response to DNA damage stimulus Inferred from expression pattern PubMed 18049476. Source: UniProtKB
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleus Inferred from direct assay Ref.36. Source: UniProtKB
Molecular_function	cysteine-type endopeptidase inhibitor activity involved in apoptotic process Inferred from direct assay Ref.7. Source: ProtInc ubiquitin-protein ligase activity Inferred from direct assay Ref.22Ref.27Ref.36. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CASP7	P55210	2	EBI-517127,EBI-523958
CASP9	P55211	5	EBI-517127,EBI-516799
DIABLO	Q9NR28	7	EBI-517127,EBI-517508
HTRA2	O43464	10	EBI-517127,EBI-517086
Htra2	Q9JIY5	4	EBI-517127,EBI-2365838	From a different organism.
RIPK4	P57078	2	EBI-517127,EBI-4422308
SEPT4	O43236-6	4	EBI-517127,EBI-4372019
SIAH1	Q8IUQ4	3	EBI-517127,EBI-747107
UBE2D1	P51668	2	EBI-517127,EBI-743540
UBE2D2	P62837	2	EBI-517127,EBI-347677
UBE2D3	P61077	2	EBI-517127,EBI-348268
UBE2N	P61088	2	EBI-517127,EBI-1052908
UBE2V1	Q13404	2	EBI-517127,EBI-1050671

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 497

497

E3 ubiquitin-protein ligase XIAP

PRO_0000122352

Regions

Repeat

26 – 93

68

BIR 1

Repeat

163 – 230

68

BIR 2

Repeat

265 – 330

66

BIR 3

Zinc finger

450 – 485

36

RING-type

Region

141 – 149

9

Interaction with caspase-7

Sites

Metal binding

300

1

Zinc By similarity

Metal binding

303

1

Zinc By similarity

Metal binding

320

1

Zinc By similarity

Metal binding

327

1

Zinc By similarity

Amino acid modifications

Modified residue

87

1

Phosphoserine; by PKB Ref.14 Ref.43

Modified residue

450

1

S-nitrosocysteine Ref.25

Cross-link

322

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.11

Cross-link

328

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.11

Natural variations

Natural variant

107

1

N → S. Ref.3
Corresponds to variant rs28382721 [ dbSNP | Ensembl ].

VAR_022282

Natural variant

133

1

S → F. Ref.3
Corresponds to variant rs28382722 [ dbSNP | Ensembl ].

VAR_022283

Natural variant

242

1

D → E. Ref.3
Corresponds to variant rs28382723 [ dbSNP | Ensembl ].

VAR_022284

Natural variant

423

1

Q → P. Ref.1 Ref.3
Corresponds to variant rs5956583 [ dbSNP | Ensembl ].

VAR_022285

Experimental info

Mutagenesis

75

1

Y → G: Loss of interaction with TAB1/MAP3K7IP1; when associated with G-75. Ref.44

Mutagenesis

80

1

V → A: Strongly reduced interaction with TAB1/MAP3K7IP1. Reduced activation of MAP3K7/TAK1. Reduced activation of NF-kappa-B. Ref.44

Mutagenesis

80

1

V → D: Loss of interaction with TAB1/MAP3K7IP1. Reduced activation of MAP3K7/TAK1. Strongly reduced activation of NF-kappa-B. Ref.44

Mutagenesis

86

1

V → E: Loss of dimerization. Reduces activation of NF-kappa-B. Ref.44

Mutagenesis

87

1

S → A: No effect on dimerization. Ref.43

Mutagenesis

87

1

S → D or E: Abolishes dimerization. Interferes with ubiquitination. Ref.43

Mutagenesis

98

1

L → G: Loss of interaction with TAB1/MAP3K7IP1; when associated with G-75. Ref.44

Mutagenesis

141

1

L → A: Reduced inhibition of caspase-3. Ref.37

Mutagenesis

147

1

V → A: Reduced inhibition of caspase-3. Ref.37

Mutagenesis

148

1

D → A: Abolishes inhibition of caspase-3. Reduced interaction with PRSS25; when associated with S-214. Ref.9 Ref.37

Mutagenesis

149

1

I → A: Reduced inhibition of caspase-3. Ref.37

Mutagenesis

151

1

D → A: Reduced inhibition of caspase-3. Ref.37

Mutagenesis

167

1

L → A: Reduced inhibition of caspase-3. Ref.37

Mutagenesis

196

1

D → A: Reduced inhibition of caspase-3. May affect protein folding and stability. Ref.37

Mutagenesis

214

1

D → S: Reduced interaction with PRSS25. Reduced interaction with PRSS25; when associated with A-148. Ref.9

Mutagenesis

259

1

N → D: Reduced interaction with PRSS25; when associated with S-314. Ref.9

Mutagenesis

310

1

W → R: Reduced interaction with PRSS25; when associated with S-314. Ref.9

Mutagenesis

314

1

E → S: Decreased interaction with DIABLO/SMAC and with PRSS25. Decreases interaction with PRSS25; when associated with D-259 or A-310. Ref.9

Mutagenesis

450

1

C → A or S: Inhibits degradation of active caspase-3. Ref.8

Mutagenesis

467

1

H → A: Loss of E3 ubiquitin-protein ligase activity. Ref.20

Sequence conflict

162

1

S → C in AAC50373. Ref.2

Secondary structure

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497

Helix Strand Turn

Details...

Helix

26 – 30

5

Helix

31 – 33

3

Beta strand

40 – 42

3

Helix

44 – 49

6

Beta strand

52 – 54

3

Beta strand

61 – 63

3

Turn

64 – 66

3

Helix

79 – 86

8

Turn

91 – 97

7

Turn

128 – 130

3

Helix

136 – 142

7

Helix

150 – 152

3

Helix

158 – 160

3

Helix

163 – 167

5

Turn

170 – 172

3

Beta strand

175 – 179

5

Helix

181 – 186

6

Beta strand

189 – 194

6

Beta strand

197 – 200

4

Turn

201 – 203

3

Beta strand

205 – 207

3

Helix

216 – 223

8

Helix

228 – 231

4

Helix

244 – 246

3

Beta strand

249 – 251

3

Beta strand

254 – 256

3

Helix

260 – 262

3

Helix

265 – 270

6

Turn

271 – 274

4

Beta strand

277 – 279

3

Helix

281 – 286

6

Beta strand

289 – 291

3

Beta strand

293 – 296

4

Beta strand

298 – 300

3

Turn

301 – 303

3

Beta strand

306 – 308

3

Beta strand

311 – 313

3

Helix

316 – 323

8

Helix

328 – 342

15

Turn

343 – 345

3

Helix

347 – 352

6

Helix

354 – 356

3

Helix

368 – 372

5

Helix

375 – 381

7

Helix

386 – 400

15

Helix

407 – 419

13

Helix

437 – 447

11

Turn

451 – 453

3

Beta strand

454 – 457

4

Beta strand

460 – 463

4

Helix

472 – 475

4

Turn

482 – 484

3

Beta strand

489 – 493

5

Sequences

	Sequence		Length	Mass (Da)
	P98170 [UniParc]. Last modified January 24, 2001. Version 2. Checksum: 9D394C16D45EB635	FASTA	497	56,685
	10 20 30 40 50 60 MTFNSFEGSK TCVPADINKE EEFVEEFNRL KTFANFPSGS PVSASTLARA GFLYTGEGDT 70 80 90 100 110 120 VRCFSCHAAV DRWQYGDSAV GRHRKVSPNC RFINGFYLEN SATQSTNSGI QNGQYKVENY 130 140 150 160 170 180 LGSRDHFALD RPSETHADYL LRTGQVVDIS DTIYPRNPAM YSEEARLKSF QNWPDYAHLT 190 200 210 220 230 240 PRELASAGLY YTGIGDQVQC FCCGGKLKNW EPCDRAWSEH RRHFPNCFFV LGRNLNIRSE 250 260 270 280 290 300 SDAVSSDRNF PNSTNLPRNP SMADYEARIF TFGTWIYSVN KEQLARAGFY ALGEGDKVKC 310 320 330 340 350 360 FHCGGGLTDW KPSEDPWEQH AKWYPGCKYL LEQKGQEYIN NIHLTHSLEE CLVRTTEKTP 370 380 390 400 410 420 SLTRRIDDTI FQNPMVQEAI RMGFSFKDIK KIMEEKIQIS GSNYKSLEVL VADLVNAQKD 430 440 450 460 470 480 SMQDESSQTS LQKEISTEEQ LRRLQEEKLC KICMDRNIAI VFVPCGHLVT CKQCAEAVDK 490 CPMCYTVITF KQKIFMS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors." Duckett C.S., Nava V.E., Gedrich R.W., Clem R.J., van Dongen J.L., Gilfillan M.C., Shiels H., Hardwick J.M., Thompson C.B. EMBO J. 15:2685-2694(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT PRO-423. Tissue: Fetal heart.
[2]	"Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes." Liston P., Roy N., Tamai K., Lefebvre C., Baird S., Cherton-Horvat G., Farahani R., McLean M., Ikeda J., Mackenzie A., Korneluk R.G. Nature 379:349-353(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal brain.
[3]	NIEHS SNPs program Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS SER-107; PHE-133; GLU-242 AND PRO-423.
[4]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Uterus.
[7]	"X-linked IAP is a direct inhibitor of cell-death proteases." Deveraux Q.L., Takahashi R., Salvesen G.S., Reed J.C. Nature 388:300-304(1997) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[8]	"Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death." Suzuki Y., Nakabayashi Y., Takahashi R. Proc. Natl. Acad. Sci. U.S.A. 98:8662-8667(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF CYS-450.
[9]	"HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins." Verhagen A.M., Silke J., Ekert P.G., Pakusch M., Kaufmann H., Connolly L.M., Day C.L., Tikoo A., Burke R., Wrobel C., Moritz R.L., Simpson R.J., Vaux D.L. J. Biol. Chem. 277:445-454(2002) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF ASP-148; ASP-214; ASN-259; TRP-310 AND GLU-314.
[10]	"Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro." MacFarlane M., Merrison W., Bratton S.B., Cohen G.M. J. Biol. Chem. 277:36611-36616(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"Identification of ubiquitination sites on the X-linked inhibitor of apoptosis protein." Shin H., Okada K., Wilkinson J.C., Solomon K.M., Duckett C.S., Reed J.C., Salvesen G.S. Biochem. J. 373:965-971(2003) [PubMed] [Europe PMC] [Abstract] Cited for: AUTOUBIQUITINATION AT LYS-322 AND LYS-328.
[12]	"A novel role for XIAP in copper homeostasis through regulation of MURR1." Burstein E., Ganesh L., Dick R.D., van De Sluis B., Wilkinson J.C., Klomp L.W., Wijmenga C., Brewer G.J., Nabel G.J., Duckett C.S. EMBO J. 23:244-254(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH COMMD1, FUNCTION.
[13]	"The mitochondrial ARTS protein promotes apoptosis through targeting XIAP." Gottfried Y., Rotem A., Lotan R., Steller H., Larisch S. EMBO J. 23:1627-1635(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SEPT4.
[14]	"Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP)." Dan H.C., Sun M., Kaneko S., Feldman R.I., Nicosia S.V., Wang H.-G., Tsang B.K., Cheng J.Q. J. Biol. Chem. 279:5405-5412(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-87, UBIQUITINATION, PROTEASOMAL DEGRADATION.
[15]	"cIAP1 Localizes to the nuclear compartment and modulates the cell cycle." Samuel T., Okada K., Hyer M., Welsh K., Zapata J.M., Reed J.C. Cancer Res. 65:210-218(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[16]	"XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome." Rigaud S., Fondaneche M.-C., Lambert N., Pasquier B., Mateo V., Soulas P., Galicier L., Le Deist F., Rieux-Laucat F., Revy P., Fischer A., de Saint Basile G., Latour S. Nature 444:110-114(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN XLP2.
[17]	"XIAP: cell death regulation meets copper homeostasis." Mufti A.R., Burstein E., Duckett C.S. Arch. Biochem. Biophys. 463:168-174(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[18]	"Nuclear localized protein-1 (Nulp1) increases cell death of human osteosarcoma cells and binds the X-linked inhibitor of apoptosis protein." Steen H., Lindholm D. Biochem. Biophys. Res. Commun. 366:432-437(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TCF25.
[19]	"IAPs: more than just inhibitors of apoptosis proteins." Dubrez-Daloz L., Dupoux A., Cartier J. Cell Cycle 7:1036-1046(2008) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[20]	"Apoptosis-inducing factor is a target for ubiquitination through interaction with XIAP." Wilkinson J.C., Wilkinson A.S., Galban S., Csomos R.A., Duckett C.S. Mol. Cell. Biol. 28:237-247(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF HIS-467, INTERACTION WITH AIFM1.
[21]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[22]	"X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization." Van Themsche C., Leblanc V., Parent S., Asselin E. J. Biol. Chem. 284:20462-20466(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN THE UBIQUITINATION OF PTEN, INTERACTION WITH PTEN.
[23]	"Molecular interaction between HAX-1 and XIAP inhibits apoptosis." Kang Y.J., Jang M., Park Y.K., Kang S., Bae K.H., Cho S., Lee C.K., Park B.C., Chi S.W., Park S.G. Biochem. Biophys. Res. Commun. 393:794-799(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HAX1.
[24]	"To fight or die - inhibitor of apoptosis proteins at the crossroad of innate immunity and death." Lopez J., Meier P. Curr. Opin. Cell Biol. 22:872-881(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[25]	"Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death." Nakamura T., Wang L., Wong C.C., Scott F.L., Eckelman B.P., Han X., Tzitzilonis C., Meng F., Gu Z., Holland E.A., Clemente A.T., Okamoto S., Salvesen G.S., Riek R., Yates J.R. III, Lipton S.A. Mol. Cell 39:184-195(2010) [PubMed] [Europe PMC] [Abstract] Cited for: S-NITROSYLATION AT CYS-450.
[26]	"Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases." Broemer M., Tenev T., Rigbolt K.T., Hempel S., Blagoev B., Silke J., Ditzel M., Meier P. Mol. Cell 40:810-822(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS AN E3 UBIQUITIN-PROTEIN LIGASE OF THE NEDD8 CONJUGATION PATHWAY.
[27]	"Regulation of the copper chaperone CCS by XIAP-mediated ubiquitination." Brady G.F., Galban S., Liu X., Basrur V., Gitlin J.D., Elenitoba-Johnson K.S., Wilson T.E., Duckett C.S. Mol. Cell. Biol. 30:1923-1936(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN THE UBIQUITINATION OF CCS, INTERACTION WITH CCS.
[28]	"IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer." Gyrd-Hansen M., Meier P. Nat. Rev. Cancer 10:561-574(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[29]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[30]	"Nondegradative ubiquitination of apoptosis inducing factor (AIF) by X-linked inhibitor of apoptosis at a residue critical for AIF-mediated chromatin degradation." Lewis E.M., Wilkinson A.S., Davis N.Y., Horita D.A., Wilkinson J.C. Biochemistry 50:11084-11096(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN THE UBIQUITINATION OF AIFM1.
[31]	"Inhibitor of apoptosis (IAP) proteins in regulation of inflammation and innate immunity." Damgaard R.B., Gyrd-Hansen M. Discov. Med. 11:221-231(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[32]	"Survivin monomer plays an essential role in apoptosis regulation." Pavlyukov M.S., Antipova N.V., Balashova M.V., Vinogradova T.V., Kopantzev E.P., Shakhparonov M.I. J. Biol. Chem. 286:23296-23307(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH BIRC5/SURVIVIN.
[33]	"The USP19 deubiquitinase regulates the stability of c-IAP1 and c-IAP2." Mei Y., Hahn A.A., Hu S., Yang X. J. Biol. Chem. 286:35380-35387(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH USP19.
[34]	"cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4)." Bertrand M.J., Lippens S., Staes A., Gilbert B., Roelandt R., De Medts J., Gevaert K., Declercq W., Vandenabeele P. PLoS ONE 6:E22356-E22356(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH RIPK1; RIPK2; RIPK3 AND RIPK4.
[35]	"IAPs: guardians of RIPK1." Darding M., Meier P. Cell Death Differ. 19:58-66(2012) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[36]	"XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling." Hanson A.J., Wallace H.A., Freeman T.J., Beauchamp R.D., Lee L.A., Lee E. Mol. Cell 45:619-628(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH TLE3 AND TCF7L2/TCF4.
[37]	"NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP." Sun C., Cai M., Gunasekera A.H., Meadows R.P., Wang H., Chen J., Zhang H., Wu W., Xu N., Ng S.-C., Fesik S.W. Nature 401:818-822(1999) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 124-240, MUTAGENESIS OF LEU-141; VAL-147; ASP-148; ILE-149; ASP-151; LEU-167 AND ASP-196.
[38]	"Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain." Liu Z., Sun C., Olejniczak E.T., Meadows R.P., Betz S.F., Oost T., Herrmann J., Wu J.C., Fesik S.W. Nature 408:1004-1008(2000) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 238-358 IN COMPLEX WITH DIABLO/SMAC.
[39]	"Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain." Huang Y., Park Y.C., Rich R.L., Segal D., Myszka D.G., Wu H. Cell 104:781-790(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 120-260 IN COMPLEX WITH CASP7.
[40]	"Mechanism of XIAP-mediated inhibition of caspase-9." Shiozaki E.N., Chai J., Rigotti D.J., Riedl S.J., Li P., Srinivasula S.M., Alnemri E.S., Fairman R., Shi Y. Mol. Cell 11:519-527(2003) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 253-350 IN COMPLEX WITH CASP9.
[41]	"Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer." Oost T.K., Sun C., Armstrong R.C., Al-Assaad A.-S., Betz S.F., Deckwerth T.L., Ding H., Elmore S.W., Meadows R.P., Olejniczak E.T., Oleksijew A., Oltersdorf T., Rosenberg S.H., Shoemaker A.R., Tomaselli K.J., Zou H., Fesik S.W. J. Med. Chem. 47:4417-4426(2004) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 241-356.
[42]	"Structure-activity based study of the Smac-binding pocket within the BIR3 domain of XIAP." Wist A.D., Gu L., Riedl S.J., Shi Y., McLendon G.L. Bioorg. Med. Chem. 15:2935-2943(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 249-354.
[43]	"Crystal structure of the BIR1 domain of XIAP in two crystal forms." Lin S.-C., Huang Y., Lo Y.-C., Lu M., Wu H. J. Mol. Biol. 372:847-854(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 10-99, PHOSPHORYLATION AT SER-87, MUTAGENESIS OF SER-87, SUBUNIT.
[44]	"XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization." Lu M., Lin S.-C., Huang Y., Kang Y.J., Rich R., Lo Y.-C., Myszka D., Han J., Wu H. Mol. Cell 26:689-702(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 10-99 IN COMPLEX WITH TAB1, FUNCTION, MUTAGENESIS OF TYR-75; VAL-80; VAL-86 AND LEU-98.
[45]	"Solution structure of the RING domain of the baculoviral IAP repeat-containing protein 4 from Homo sapiens." RIKEN structural genomics initiative (RSGI) Submitted (MAR-2008) to the PDB data bank Cited for: STRUCTURE BY NMR OF 427-497.
+	Additional computationally mapped references.

Web resources

GeneReviews

BIRC4base

XIAP mutation db

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U32974 mRNA. Translation: AAC50518.1.
U45880 mRNA. Translation: AAC50373.1.
AY886519 Genomic DNA. Translation: AAW62257.1.
AL121601 Genomic DNA. Translation: CAB95312.1.
CH471107 Genomic DNA. Translation: EAX11858.1.
CH471107 Genomic DNA. Translation: EAX11859.1.
CH471107 Genomic DNA. Translation: EAX11860.1.
CH471107 Genomic DNA. Translation: EAX11861.1.
BC032729 mRNA. Translation: AAH32729.1.

IPI

IPI00303890.

PIR

S69544.

RefSeq

NP_001158.2. NM_001167.3.
NP_001191330.1. NM_001204401.1.

UniGene

Hs.356076.
Hs.736565.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1C9Q	NMR	-	A	124-240	[»]
1F9X	NMR	-	A	241-356	[»]
1G3F	NMR	-	A	241-356	[»]
1G73	X-ray	2.00	C/D	238-358	[»]
1I3O	X-ray	2.70	E/F	124-240	[»]
1I4O	X-ray	2.40	C/D	120-260	[»]
1I51	X-ray	2.45	E/F	124-240	[»]
1KMC	X-ray	2.90	C/D	124-242	[»]
1NW9	X-ray	2.40	A	253-350	[»]
1TFQ	NMR	-	A	241-356	[»]
1TFT	NMR	-	A	241-356	[»]
2ECG	NMR	-	A	430-497	[»]
2JK7	X-ray	2.82	A	241-356	[»]
2KNA	NMR	-	A	357-449	[»]
2OPY	X-ray	2.80	A	249-354	[»]
2OPZ	X-ray	3.00	A/B/C/D	249-357	[»]
2POI	X-ray	1.80	A	10-99	[»]
2POP	X-ray	3.10	B/D	10-100	[»]
2QRA	X-ray	2.50	A/B/C/D	10-99	[»]
2VSL	X-ray	2.10	A	250-345	[»]
3CLX	X-ray	2.70	A/B/C/D	241-356	[»]
3CM2	X-ray	2.50	A/B/C/D/E/F/G/H/I/J	241-356	[»]
3CM7	X-ray	3.10	A/B/C/D	241-356	[»]
3EYL	X-ray	3.00	A/B	241-356	[»]
3G76	X-ray	3.00	A/B/C/D/E/F/G/H	241-356	[»]
3HL5	X-ray	1.80	A/B	256-346	[»]
3UW4	X-ray	1.79	A	338-348	[»]
3UW5	X-ray	1.71	A/B	296-348	[»]
4EC4	X-ray	3.30	A/B/C/D/E/F/G/J/K/L	241-356	[»]
4HY0	X-ray	2.84	A/B/C/D/E/F/G/H	238-357	[»]
4IC2	X-ray	2.20	A/B	429-497	[»]
4IC3	X-ray	1.78	A/B	429-497	[»]

ProteinModelPortal

P98170.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-27626N.

IntAct

P98170. 32 interactions.

MINT

MINT-141734.

STRING

9606.ENSP00000347858.

Protein family/group databases

MEROPS

I32.004.

PTM databases

PhosphoSite

P98170.

Polymorphism databases

DMDM

12643387.

Proteomic databases

PaxDb

P98170.

PeptideAtlas

P98170.

PRIDE

P98170.

Protocols and materials databases

DNASU

331.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000355640; ENSP00000347858; ENSG00000101966.
ENST00000371199; ENSP00000360242; ENSG00000101966.
ENST00000434753; ENSP00000395230; ENSG00000101966.

GeneID

331.

KEGG

hsa:331.

UCSC

uc004etx.3. human.

Organism-specific databases

CTD

331.

GeneCards

GC0XP122993.

HGNC

HGNC:592. XIAP.

HPA

CAB009203.

MIM

300079. gene.
300635. phenotype.

neXtProt

NX_P98170.

Orphanet

2442. X-linked lymphoproliferative disease.

PharmGKB

PA25361.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG243347.

HOGENOM

HOG000232059.

HOVERGEN

HBG004848.

InParanoid

P98170.

KO

K04725.

OMA

TDWKPSE.

PhylomeDB

P98170.

Enzyme and pathway databases

Pathway_Interaction_DB

bmppathway. BMP receptor signaling.
caspase_pathway. Caspase cascade in apoptosis.
p75ntrpathway. p75(NTR)-mediated signaling.
tgfbrpathway. TGF-beta receptor signaling.

Reactome

REACT_578. Apoptosis.

Gene expression databases

ArrayExpress

P98170.

Bgee

P98170.

CleanEx

HS_XIAP.

Genevestigator

P98170.

GermOnline

ENSG00000101966. Homo sapiens.

Family and domain databases

Gene3D

1.10.1170.10. 4 hits.

InterPro

IPR001370. BIR.
IPR001841. Znf_RING.
[Graphical view]

Pfam

PF00653. BIR. 3 hits.
[Graphical view]

SMART

SM00238. BIR. 3 hits.
SM00184. RING. 1 hit.
[Graphical view]

PROSITE

PS01282. BIR_REPEAT_1. 3 hits.
PS50143. BIR_REPEAT_2. 3 hits.
PS00518. ZF_RING_1. False negative.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P98170.

ChEMBL

CHEMBL4198.

ChiTaRS

XIAP. human.

EvolutionaryTrace

P98170.

GenomeRNAi

331.

NextBio

1365.

PMAP-CutDB

P98170.

SOURCE

Search...

Entry information

Entry name

XIAP_HUMAN

Accession

Primary (citable) accession number: P98170
Secondary accession number(s): D3DTF2, Q9NQ14

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	January 24, 2001
Last modified:	May 1, 2013
This is version 146 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.