Q13489 (BIRC3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Baculoviral IAP repeat-containing protein 3
EC=6.3.2.-

Alternative name(s):
Apoptosis inhibitor 2
Short name=API2
C-IAP2
IAP homolog C
Inhibitor of apoptosis protein 1
Short name=IAP-1
Short name=hIAP-1
Short name=hIAP1
RING finger protein 49
TNFR2-TRAF-signaling complex protein 1

Gene names

Name:	BIRC3
Synonyms:	API2, IAP1, MIHC, RNF49

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	604 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, mitogenic kinase signaling and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF1, and BCL10. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). 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. Ref.14
Enzyme regulation	USP19 regulates the stability of BIRC3/c-IAP2 by preventing its ubiquitination. Ref.13
Subunit structure	Interacts with DIABLO/SMAC and with PRSS25; these interactions inhibit apoptotic suppressor activity. The BIR motifs region interacts with TNF receptor associated factors 1 and 2 (TRAF1 and TRAF2) to form a heteromeric complex, which is then recruited to the tumor necrosis factor receptor 2 (TNFR2). Interacts with RIP1, RIP2, RIP3, RIP4 and USP19. Ref.13 Ref.14
Subcellular location	Cytoplasm. Nucleus Ref.8.
Tissue specificity	Highly expressed in fetal lung, and kidney. In the adult, expression is mainly seen in lymphoid tissues, including spleen, thymus and peripheral blood lymphocytes.
Post-translational modification	Auto-ubiquitinated and degraded by the proteasome in apoptotic cells.
Involvement in disease	A chromosomal aberration involving BIRC3 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with MALT1. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma.
Sequence similarities	Belongs to the IAP family. Contains 3 BIR repeats. Contains 1 CARD domain. Contains 1 RING-type zinc finger.

Ontologies

Keywords
Biological process	Apoptosis Ubl conjugation pathway
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Domain	Repeat Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Ligase
PTM	Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	NIK/NF-kappaB cascade Traceable author statement Ref.11. Source: UniProtKB apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cell surface receptor signaling pathway Traceable author statement Ref.1. Source: ProtInc necroptosis Inferred from electronic annotation. Source: Compara negative regulation of apoptotic process Traceable author statement Ref.2. Source: ProtInc negative regulation of necroptosis Inferred from electronic annotation. Source: Compara negative regulation of phosphorylation Inferred from electronic annotation. Source: Compara negative regulation of reactive oxygen species metabolic process Inferred from electronic annotation. Source: Compara positive regulation of I-kappaB kinase/NF-kappaB cascade Traceable author statement Ref.11. Source: UniProtKB regulation of RIG-I signaling pathway Traceable author statement Ref.10. Source: UniProtKB regulation of cysteine-type endopeptidase activity Traceable author statement Ref.11. Source: UniProtKB regulation of inflammatory response Traceable author statement Ref.12. Source: UniProtKB regulation of innate immune response Traceable author statement Ref.12. Source: UniProtKB regulation of nucleotide-binding oligomerization domain containing signaling pathway Traceable author statement Ref.10. Source: UniProtKB regulation of toll-like receptor signaling pathway Traceable author statement Ref.10. Source: UniProtKB
Cellular_component	cytoplasm Inferred from direct assay Ref.8PubMed 16123224. Source: UniProtKB nucleus Inferred from direct assay Ref.8PubMed 16123224. Source: UniProtKB
Molecular_function	ubiquitin-protein ligase activity Inferred from direct assay PubMed 16395405. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DIABLO	Q9NR28	2	EBI-517709,EBI-517508
RIPK1	Q13546	3	EBI-517709,EBI-358507
RIPK2	O43353	3	EBI-517709,EBI-358522
RIPK3	Q9Y572	3	EBI-517709,EBI-298250
RIPK4	P57078	3	EBI-517709,EBI-4422308
TRAF2	Q12933	5	EBI-517709,EBI-355744

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 604

604

Baculoviral IAP repeat-containing protein 3

PRO_0000122349

Regions

Repeat

29 – 96

68

BIR 1

Repeat

169 – 235

67

BIR 2

Repeat

255 – 322

68

BIR 3

Domain

439 – 529

91

CARD

Zinc finger

557 – 592

36

RING-type

Sites

Metal binding

292

1

Zinc By similarity

Metal binding

295

1

Zinc By similarity

Metal binding

312

1

Zinc By similarity

Metal binding

319

1

Zinc By similarity

Site

442 – 443

2

Breakpoint for translocation to form BIRC3-MALT1

Natural variations

Natural variant

260

1

K → R. Ref.5
Corresponds to variant rs2276113 [ dbSNP | Ensembl ].

VAR_021069

Natural variant

386

1

V → M.
Corresponds to variant rs12222256 [ dbSNP | Ensembl ].

VAR_049536

Natural variant

401

1

R → K. Ref.5
Corresponds to variant rs17881197 [ dbSNP | Ensembl ].

VAR_021070

Experimental info

Sequence conflict

18

1

N → Y in AAC83232. Ref.4

Sequence conflict

119

1

N → H in AAC50371. Ref.2

Sequence conflict

153

1

D → E in AAC50371. Ref.2

Sequence conflict

163

1

H → P in AAC50371. Ref.2

Sequence conflict

165

1

A → P in AAC50371. Ref.2

Sequence conflict

191

1

K → R in AAC50371. Ref.2

Sequence conflict

364

1

F → L in AAC50371. Ref.2

Sequence conflict

552

1

Q → P in AAC50371. Ref.2

Secondary structure

1

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604

Helix Strand Turn

Details...

Helix

28 – 34

7

Helix

35 – 38

4

Helix

47 – 52

6

Beta strand

55 – 57

3

Beta strand

64 – 66

3

Turn

67 – 69

3

Helix

82 – 89

8

Turn

94 – 97

4

Helix

250 – 252

3

Helix

255 – 260

6

Helix

261 – 264

4

Helix

273 – 278

6

Beta strand

281 – 285

5

Turn

286 – 288

3

Beta strand

289 – 292

4

Turn

293 – 295

3

Beta strand

298 – 301

4

Helix

308 – 315

8

Helix

320 – 334

15

Helix

544 – 555

12

Turn

558 – 560

3

Beta strand

561 – 564

4

Beta strand

567 – 570

4

Beta strand

575 – 577

3

Turn

579 – 581

3

Helix

582 – 584

3

Beta strand

589 – 591

3

Beta strand

597 – 600

4

Sequences

	Sequence		Length	Mass (Da)
	Q13489 [UniParc]. Last modified November 1, 1997. Version 2. Checksum: 8581A00BA9AAB4A7	FASTA	604	68,372
	10 20 30 40 50 60 MNIVENSIFL SNLMKSANTF ELKYDLSCEL YRMSTYSTFP AGVPVSERSL ARAGFYYTGV 70 80 90 100 110 120 NDKVKCFCCG LMLDNWKRGD SPTEKHKKLY PSCRFVQSLN SVNNLEATSQ PTFPSSVTNS 130 140 150 160 170 180 THSLLPGTEN SGYFRGSYSN SPSNPVNSRA NQDFSALMRS SYHCAMNNEN ARLLTFQTWP 190 200 210 220 230 240 LTFLSPTDLA KAGFYYIGPG DRVACFACGG KLSNWEPKDN AMSEHLRHFP KCPFIENQLQ 250 260 270 280 290 300 DTSRYTVSNL SMQTHAARFK TFFNWPSSVL VNPEQLASAG FYYVGNSDDV KCFCCDGGLR 310 320 330 340 350 360 CWESGDDPWV QHAKWFPRCE YLIRIKGQEF IRQVQASYPH LLEQLLSTSD SPGDENAESS 370 380 390 400 410 420 IIHFEPGEDH SEDAIMMNTP VINAAVEMGF SRSLVKQTVQ RKILATGENY RLVNDLVLDL 430 440 450 460 470 480 LNAEDEIREE ERERATEEKE SNDLLLIRKN RMALFQHLTC VIPILDSLLT AGIINEQEHD 490 500 510 520 530 540 VIKQKTQTSL QARELIDTIL VKGNIAATVF RNSLQEAEAV LYEHLFVQQD IKYIPTEDVS 550 560 570 580 590 600 DLPVEEQLRR LQEERTCKVC MDKEVSIVFI PCGHLVVCKD CAPSLRKCPI CRSTIKGTVR TFLS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins." Rothe M., Pan M.-G., Henzel W.J., Ayres T.M., Goeddel D.V. Cell 83:1243-1252(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[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: Liver.
[3]	"Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors." Uren A.G., Pakusch M., Hawkins C.J., Puls K.L., Vaux D.L. Proc. Natl. Acad. Sci. U.S.A. 93:4974-4978(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal liver.
[4]	"Vascular endothelial genes that are responsive to tumor necrosis factor-alpha in vitro are expressed in atherosclerotic lesions, including inhibitor of apoptosis protein-1, stannin, and two novel genes." Horrevoets A.J.G., Fontijn R.D., van Zonneveld A.J., de Vries C.J.M., ten Cate J.W., Pannekoek H. Blood 93:3418-3431(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	NIEHS SNPs program Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ARG-260 AND LYS-401.
[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: Lymph.
[7]	"Structure of the MLT gene and molecular characterization of the genomic breakpoint junctions in the t(11;18)(q21;q21) of marginal zone B-cell lymphomas of MALT type." Baens M., Steyls A., Dierlamm J., De Wolf-Peeters C., Marynen P. Genes Chromosomes Cancer 29:281-291(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 362-441.
[8]	"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.
[9]	"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.
[10]	"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.
[11]	"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.
[12]	"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.
[13]	"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: ENZYME REGULATION, INTERACTION WITH USP19.
[14]	"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: FUNCTION IN THE UBIQUITINATION OF RIPK1; RIPK2; RIPK3 AND RIPK4, INTERACTION WITH RIPK1; RIPK2; RIPK3 AND RIPK4.
[15]	"IAPs: guardians of RIPK1." Darding M., Meier P. Cell Death Differ. 19:58-66(2012) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L49432 mRNA. Translation: AAC41943.1.
U45878 mRNA. Translation: AAC50371.1.
U37546 mRNA. Translation: AAC50507.1.
AF070674 mRNA. Translation: AAC83232.1.
AY764389 Genomic DNA. Translation: AAU88144.1.
BC037420 mRNA. Translation: AAH37420.1.
AF178945 Genomic DNA. Translation: AAG09369.1.

IPI

IPI00013409.

PIR

S68449.

RefSeq

NP_001156.1. NM_001165.4.
NP_892007.1. NM_182962.2.

UniGene

Hs.127799.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2UVL	X-ray	1.91	A/B	244-337	[»]
3EB5	X-ray	2.00	A	536-604	[»]
3EB6	X-ray	3.40	A	536-604	[»]
3M0A	X-ray	2.61	D	26-99	[»]
3M0D	X-ray	2.80	D	26-99	[»]

ProteinModelPortal

Q13489.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-33720N.

IntAct

Q13489. 16 interactions.

STRING

9606.ENSP00000263464.

Protein family/group databases

MEROPS

I32.003.

PTM databases

PhosphoSite

Q13489.

Polymorphism databases

DMDM

2497236.

Proteomic databases

PaxDb

Q13489.

PRIDE

Q13489.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000263464; ENSP00000263464; ENSG00000023445.
ENST00000532808; ENSP00000432907; ENSG00000023445.

GeneID

330.

KEGG

hsa:330.

UCSC

uc001pgx.3. human.

Organism-specific databases

CTD

330.

GeneCards

GC11P102188.

HGNC

HGNC:591. BIRC3.

HPA

HPA002317.

MIM

601721. gene.

neXtProt

NX_Q13489.

Orphanet

52417. MALT lymphoma.

PharmGKB

PA25360.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG243347.

HOGENOM

HOG000232059.

HOVERGEN

HBG004848.

InParanoid

Q13489.

KO

K16060.

OMA

ENSGYFS.

OrthoDB

EOG4K3KVW.

PhylomeDB

Q13489.

Enzyme and pathway databases

Pathway_Interaction_DB

caspase_pathway. Caspase cascade in apoptosis.
ceramidepathway. Ceramide signaling pathway.
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
p75ntrpathway. p75(NTR)-mediated signaling.
tnfpathway. TNF receptor signaling pathway.

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q13489.

Bgee

Q13489.

CleanEx

HS_BIRC3.

Genevestigator

Q13489.

GermOnline

ENSG00000023445. Homo sapiens.

Family and domain databases

Gene3D

1.10.1170.10. 4 hits.
1.10.533.10. 1 hit.

InterPro

IPR001370. BIR.
IPR001315. CARD.
IPR011029. DEATH-like_dom.
IPR001841. Znf_RING.
[Graphical view]

Pfam

PF00653. BIR. 3 hits.
PF00619. CARD. 1 hit.
[Graphical view]

SMART

SM00238. BIR. 3 hits.
SM00114. CARD. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]

SUPFAM

SSF47986. DEATH_like. 1 hit.

PROSITE

PS01282. BIR_REPEAT_1. 3 hits.
PS50143. BIR_REPEAT_2. 3 hits.
PS50209. CARD. 1 hit.
PS00518. ZF_RING_1. False negative.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q13489.

ChEMBL

CHEMBL5335.

ChiTaRS

BIRC3. human.

EvolutionaryTrace

Q13489.

GenomeRNAi

330.

NextBio

1359.

PMAP-CutDB

Q13489.

SOURCE

Search...

Entry information

Entry name

BIRC3_HUMAN

Accession

Primary (citable) accession number: Q13489
Secondary accession number(s): Q16628, Q9HC27, Q9UP46

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1997
Last modified:	May 1, 2013
This is version 135 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.