PDBsum entry 2poi

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Signaling protein/apoptosis PDB id
Protein chain
78 a.a. *
Waters ×85
* Residue conservation analysis
PDB id:
Name: Signaling protein/apoptosis
Title: Crystal structure of xiap bir1 domain (i222 form)
Structure: Baculoviral iap repeat-containing protein 4. Chain: a. Fragment: bir1 domain. Synonym: inhibitor of apoptosis protein 3, x-linked inhibitor of apoptosis protein, x-linked iap, iap-like protein, hilp. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: birc4, api3, iap3, xiap. Expressed in: escherichia coli k12. Expression_system_taxid: 83333.
1.80Å     R-factor:   0.203     R-free:   0.213
Authors: S.Lin
Key ref:
M.Lu et al. (2007). XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell, 26, 689-702. PubMed id: 17560374 DOI: 10.1016/j.molcel.2007.05.006
26-Apr-07     Release date:   03-Jul-07    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P98170  (XIAP_HUMAN) -  E3 ubiquitin-protein ligase XIAP
497 a.a.
78 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain


DOI no: 10.1016/j.molcel.2007.05.006 Mol Cell 26:689-702 (2007)
PubMed id: 17560374  
XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization.
M.Lu, S.C.Lin, Y.Huang, Y.J.Kang, R.Rich, Y.C.Lo, D.Myszka, J.Han, H.Wu.
In addition to caspase inhibition, X-linked inhibitor of apoptosis (XIAP) induces NF-kappaB and MAP kinase activation during TGF-b and BMP receptor signaling and upon overexpression. Here we show that the BIR1 domain of XIAP, which has no previously ascribed function, directly interacts with TAB1 to induce NF-kappaB activation. TAB1 is an upstream adaptor for the activation of the kinase TAK1, which in turn couples to the NF-kappaB pathway. We report the crystal structures of BIR1, TAB1, and the BIR1/TAB1 complex. The BIR1/TAB1 structure reveals a striking butterfly-shaped dimer and the detailed interaction between BIR1 and TAB1. Structure-based mutagenesis and knockdown of TAB1 show unambiguously that the BIR1/TAB1 interaction is crucial for XIAP-induced TAK1 and NF-kappaB activation. We show that although not interacting with BIR1, Smac, the antagonist for caspase inhibition by XIAP, also inhibits the XIAP/TAB1 interaction. Disruption of BIR1 dimerization abolishes XIAP-mediated NF-kappaB activation, implicating a proximity-induced mechanism for TAK1 activation.
  Selected figure(s)  
Figure 1.
Figure 1. Biochemical Analysis of the Interaction between the BIR1 Domain of XIAP and the N-Terminal Domain of TAB1
(A) Comigration of BIR1 and TAB1 N-terminal domain on gel filtration chromatography.
(B) Duplicate responses (left) and isotherms (right) for a 2-fold dilution series (0.143–18.25 μM) of TAB1 binding to surface-tethered BIR1 in an SPR experiment.
(C) Duplicate responses (left) and isotherms (right) for a 2-fold dilution series (0.143–18.25 μM) of TAB1 binding to surface-tethered BIR1-3 in an SPR experiment.
Figure 5.
Figure 5. TAB1 Does Not Have Phosphatase Activity
(A) Superposition of human TAB1 (yellow), human phosphatase PP2Cα (green), and bacterial phosphatase PstP (pink).
(B) Superposition of the active sites of TAB1 (yellow) and PP2Cα (green). Two metal ions and one phosphate ion are bound at the PP2Cα active site. Residues important for metal ion coordination and catalysis are labeled in black for TAB1 and green for PP2Cα.
(C) Only one Mn^2+ ion is bound at the TAB1 active site when soaked with MnCl[2]. The F[o] − F[c] map is shown at 10σ level.
(D) Electrostatic surface of the PP2Cα active site. The location of the bound phosphate ion is shown.
(E) Electrostatic surface of the same region in TAB1.
  The above figures are reprinted by permission from Cell Press: Mol Cell (2007, 26, 689-702) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21354220 L.Flanagan, J.Sebastia, M.E.Delgado, J.C.Lennon, and M.Rehm (2011).
Dimerization of Smac is crucial for its mitochondrial retention by XIAP subsequent to mitochondrial outer membrane permeabilization.
  Biochim Biophys Acta, 1813, 819-826.  
21340509 M.Orzáez, A.Gortat, M.Sancho, R.J.Carbajo, A.Pineda-Lucena, Y.Palacios-Rodríguez, and E.Pérez-Payá (2011).
Characterization of dequalinium as a XIAP antagonist that targets the BIR2 domain.
  Apoptosis, 16, 460-467.  
20660790 A.H.Filipovich, K.Zhang, A.L.Snow, and R.A.Marsh (2010).
X-linked lymphoproliferative syndromes: brothers or distant cousins?
  Blood, 116, 3398-3408.  
20385093 C.Zheng, V.Kabaleeswaran, Y.Wang, G.Cheng, and H.Wu (2010).
Crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes: affinity, specificity, and regulation.
  Mol Cell, 38, 101-113.
PDB codes: 3m06 3m0a 3m0d
20704571 D.C.Altieri (2010).
Survivin and IAP proteins in cell-death mechanisms.
  Biochem J, 430, 199-205.  
20131005 K.K.Chung (2010).
Modulation of pro-survival proteins by S-nitrosylation: implications for neurodegeneration.
  Apoptosis, 15, 1364-1370.  
21364655 L.Flanagan, J.Sebastià, L.P.Tuffy, A.Spring, A.Lichawska, M.Devocelle, J.H.Prehn, and M.Rehm (2010).
XIAP impairs Smac release from the mitochondria during apoptosis.
  Cell Death Dis, 1, e49.  
20837698 M.Dougan, S.Dougan, J.Slisz, B.Firestone, M.Vanneman, D.Draganov, G.Goyal, W.Li, D.Neuberg, R.Blumberg, N.Hacohen, D.Porter, L.Zawel, and G.Dranoff (2010).
IAP inhibitors enhance co-stimulation to promote tumor immunity.
  J Exp Med, 207, 2195-2206.  
20651737 M.Gyrd-Hansen, and P.Meier (2010).
IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer.
  Nat Rev Cancer, 10, 561-574.  
20817427 P.D.Mace, and S.J.Riedl (2010).
Molecular cell death platforms and assemblies.
  Curr Opin Cell Biol, 22, 828-836.  
19373243 P.D.Mace, S.Shirley, and C.L.Day (2010).
Assembling the building blocks: structure and function of inhibitor of apoptosis proteins.
  Cell Death Differ, 17, 46-53.  
19590513 S.Galbán, and C.S.Duckett (2010).
XIAP as a ubiquitin ligase in cellular signaling.
  Cell Death Differ, 17, 54-60.  
19916060 S.K.Hui, M.K.Tse, Y.Yang, B.C.Wong, and K.H.Sze (2010).
Backbone and side-chain 1H, 13C and 15N assignments of the ubiquitin-associated domain of human X-linked inhibitor of apoptosis protein.
  Biomol NMR Assign, 4, 13-15.
PDB code: 2kna
20129247 S.Mehrotra, L.R.Languino, C.M.Raskett, A.M.Mercurio, T.Dohi, and D.C.Altieri (2010).
IAP regulation of metastasis.
  Cancer Cell, 17, 53-64.  
20584313 T.W.Owens, F.M.Foster, J.Tanianis-Hughes, J.Y.Cheung, L.Brackenbury, and C.H.Streuli (2010).
Analysis of inhibitor of apoptosis protein family expression during mammary gland development.
  BMC Dev Biol, 10, 71.  
19273858 A.H.Tsang, Y.I.Lee, H.S.Ko, J.M.Savitt, O.Pletnikova, J.C.Troncoso, V.L.Dawson, T.M.Dawson, and K.K.Chung (2009).
S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease.
  Proc Natl Acad Sci U S A, 106, 4900-4905.  
19667203 A.Krieg, R.G.Correa, J.B.Garrison, G.Le Negrate, K.Welsh, Z.Huang, W.T.Knoefel, and J.C.Reed (2009).
XIAP mediates NOD signaling via interaction with RIP2.
  Proc Natl Acad Sci U S A, 106, 14524-14529.  
19660030 C.D.Moore, H.Wu, B.Bolaños, S.Bergqvist, A.Brooun, T.Pauly, and D.Nowlin (2009).
Structural and biophysical characterization of XIAP BIR3 G306E mutant: insights in protein dynamics and application for fragment-based drug design.
  Chem Biol Drug Des, 74, 212-223.  
19500649 H.M.Bramlett, O.Furones-Alonso, G.Lotocki, A.Rodriguez-Paez, J.Sanchez-Molano, and R.W.Keane (2009).
Sex differences in XIAP cleavage after traumatic brain injury in the rat.
  Neurosci Lett, 461, 49-53.  
19909372 H.Shinohara, and T.Kurosaki (2009).
Comprehending the complex connection between PKCbeta, TAK1, and IKK in BCR signaling.
  Immunol Rev, 232, 300-318.  
19531477 J.R.Neil, M.Tian, and W.P.Schiemann (2009).
X-linked Inhibitor of Apoptosis Protein and Its E3 Ligase Activity Promote Transforming Growth Factor-{beta}-mediated Nuclear Factor-{kappa}B Activation during Breast Cancer Progression.
  J Biol Chem, 284, 21209-21217.  
19355825 L.Q.Gu, F.Y.Li, L.Zhao, Y.Liu, X.X.Zang, T.X.Wang, H.P.Chen, G.Ning, and Y.J.Zhao (2009).
BRAFV600E mutation and X-linked inhibitor of apoptosis expression in papillary thyroid carcinoma.
  Thyroid, 19, 347-354.  
19877056 M.Ferretti, M.Gattorno, A.Chiocchetti, R.Mesturini, E.Orilieri, T.Bensi, M.P.Sormani, G.Cappellano, E.Cerutti, S.Nicola, A.Biava, C.Bardelli, S.Federici, I.Ceccherini, M.Baldi, C.Santoro, I.Dianzani, A.Martini, and U.Dianzani (2009).
The 423Q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever.
  Arthritis Rheum, 60, 3476-3484.  
19735291 M.Kairisalo, L.Korhonen, M.Sepp, P.Pruunsild, J.P.Kukkonen, J.Kivinen, T.Timmusk, K.Blomgren, and D.Lindholm (2009).
NF-kappaB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein.
  Eur J Neurosci, 30, 958-966.  
19003982 S.Fulda (2009).
Tumor resistance to apoptosis.
  Int J Cancer, 124, 511-515.  
19039324 S.Fulda (2009).
Inhibitor of apoptosis proteins in hematological malignancies.
  Leukemia, 23, 467-476.  
19130230 S.Fulda (2009).
Cell death in hematological tumors.
  Apoptosis, 14, 409-423.  
19298593 S.Fulda (2009).
Therapeutic opportunities for counteracting apoptosis resistance in childhood leukaemia.
  Br J Haematol, 145, 441-454.  
  19966933 Y.Dai, T.S.Lawrence, and L.Xu (2009).
Overcoming cancer therapy resistance by targeting inhibitors of apoptosis proteins and nuclear factor-kappa B.
  Am J Transl Res, 1, 1.  
18697935 D.J.Mahoney, H.H.Cheung, R.L.Mrad, S.Plenchette, C.Simard, E.Enwere, V.Arora, T.W.Mak, E.C.Lacasse, J.Waring, and R.G.Korneluk (2008).
Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation.
  Proc Natl Acad Sci U S A, 105, 11778-11783.  
18931692 E.C.LaCasse, D.J.Mahoney, H.H.Cheung, S.Plenchette, S.Baird, and R.G.Korneluk (2008).
IAP-targeted therapies for cancer.
  Oncogene, 27, 6252-6275.  
18946021 J.M.Rumble, and C.S.Duckett (2008).
Diverse functions within the IAP family.
  J Cell Sci, 121, 3505-3507.  
18769721 L.D.Bauler, C.S.Duckett, and M.X.O'Riordan (2008).
XIAP regulates cytosol-specific innate immunity to Listeria infection.
  PLoS Pathog, 4, e1000142.  
18931663 M.Gyrd-Hansen, M.Darding, M.Miasari, M.M.Santoro, L.Zender, W.Xue, T.Tenev, P.C.da Fonseca, M.Zvelebil, J.M.Bujnicki, S.Lowe, J.Silke, and P.Meier (2008).
IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis.
  Nat Cell Biol, 10, 1309-1317.  
18829460 M.Inagaki, E.Omori, J.Y.Kim, Y.Komatsu, G.Scott, M.K.Ray, G.Yamada, K.Matsumoto, Y.Mishina, and J.Ninomiya-Tsuji (2008).
TAK1-binding Protein 1, TAB1, Mediates Osmotic Stress-induced TAK1 Activation but Is Dispensable for TAK1-mediated Cytokine Signaling.
  J Biol Chem, 283, 33080-33086.  
18854135 M.X.O'Riordan, L.D.Bauler, F.L.Scott, and C.S.Duckett (2008).
Inhibitor of apoptosis proteins in eukaryotic evolution and development: a model of thematic conservation.
  Dev Cell, 15, 497-508.  
18620520 S.M.Langemeijer, Graaf, and J.H.Jansen (2008).
IAPs as therapeutic targets in haematological malignancies.
  Expert Opin Ther Targets, 12, 981-993.  
18439892 S.M.Srinivasula, and J.D.Ashwell (2008).
IAPs: what's in a name?
  Mol Cell, 30, 123-135.  
18955972 S.W.Tait, and D.R.Green (2008).
Caspase-independent cell death: leaving the set without the final cut.
  Oncogene, 27, 6452-6461.  
19047096 Y.Dai, M.Liu, W.Tang, J.DeSano, E.Burstein, M.Davis, K.Pienta, T.Lawrence, and L.Xu (2008).
Molecularly targeted radiosensitization of human prostate cancer by modulating inhibitor of apoptosis.
  Clin Cancer Res, 14, 7701-7710.  
18552156 Y.Song, L.Coleman, J.Shi, H.Beppu, K.Sato, K.Walsh, J.Loscalzo, and Y.Y.Zhang (2008).
Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice.
  Am J Physiol Heart Circ Physiol, 295, H677-H690.  
17698078 S.C.Lin, Y.Huang, Y.C.Lo, M.Lu, and H.Wu (2007).
Crystal structure of the BIR1 domain of XIAP in two crystal forms.
  J Mol Biol, 372, 847-854.
PDB code: 2qra
17724022 Z.Gao, Y.Tian, J.Wang, Q.Yin, H.Wu, Y.M.Li, and X.Jiang (2007).
A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo.
  J Biol Chem, 282, 30718-30727.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.