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Apoptosis PDB id
1dg6
Jmol
Contents
Protein chain
149 a.a. *
Metals
_CL
_ZN
Waters ×226
* Residue conservation analysis
PDB id:
1dg6
Name: Apoptosis
Title: Crystal structure of apo2l/trail
Structure: Apo2l/tnf-related apopotis inducing ligand (trail chain: a. Fragment: trimeric jelly-roll domain of apo2l. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: human placenta. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: human placenta
Resolution:
1.30Å     R-factor:   0.141     R-free:   0.197
Authors: S.G.Hymowitz,M.P.O'Connell,M.H.Ultsch,A.M.De Vos,R.F.Kelley
Key ref:
S.G.Hymowitz et al. (2000). A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. Biochemistry, 39, 633-640. PubMed id: 10651627 DOI: 10.1021/bi992242l
Date:
23-Nov-99     Release date:   26-Jan-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P50591  (TNF10_HUMAN) -  Tumor necrosis factor ligand superfamily member 10
Seq:
Struc: 		281 a.a.
149 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     immune response   1 term 
  Biochemical function     protein binding     2 terms  

 

 
DOI no: 10.1021/bi992242l Biochemistry 39:633-640 (2000)
PubMed id: 10651627  
 
 
A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL.
S.G.Hymowitz, M.P.O'Connell, M.H.Ultsch, A.Hurst, K.Totpal, A.Ashkenazi, A.M.de Vos, R.F.Kelley.
 
  ABSTRACT  
 
Apoptosis-inducing ligand 2 (Apo2L, also called TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in a variety of human tumor cell lines but not in normal cells [Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R., Smith, T. D., Rauch, C., Smith, C. A., and Goodwin, R. G. (1995) Immunity 3, 673-682; Pitti, R. M., Marsters, S. A., Ruppert, S., Donahue, C. J., Moore, A., and Ashkenazi, A. (1996) J. Biol. Chem. 271, 12687-12690]. Here we describe the structure of Apo2L at 1.3 A resolution and use alanine-scanning mutagenesis to map the receptor contact regions. The structure reveals a homotrimeric protein that resembles TNF with receptor-binding epitopes at the interface between monomers. A zinc ion is buried at the trimer interface, coordinated by the single cysteine residue of each monomer. The zinc ion is required for maintaining the native structure and stability and, hence, the biological activity of Apo2L. This is the first example of metal-dependent oligomerization and function of a cytokine.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20531300 F.Gonzalvez, and A.Ashkenazi (2010).
New insights into apoptosis signaling by Apo2L/TRAIL.
  Oncogene, 29, 4752-4765.  
20585844 J.Y.Chang, N.J.Xiao, M.Zhu, J.Zhang, E.Hoff, S.J.Russell, V.Katta, and S.J.Shire (2010).
Leachables from saline-containing IV bags can alter therapeutic protein properties.
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20945485 L.Speciner, E.Mallon, S.Leung, M.W.Laird, and O.Esue (2010).
Characterization of a nutrient feed precipitate from an E. coli fermentation process.
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20515924 M.S.Lee, R.P.Cherla, E.K.Lentz, D.Leyva-Illades, and V.L.Tesh (2010).
Signaling through C/EBP homologous protein and death receptor 5 and calpain activation differentially regulate THP-1 cell maturation-dependent apoptosis induced by Shiga toxin type 1.
  Infect Immun, 78, 3378-3391.  
20033783 P.M.Eimon, and A.Ashkenazi (2010).
The zebrafish as a model organism for the study of apoptosis.
  Apoptosis, 15, 331-349.  
19522538 C.Zhan, Q.Yan, Y.Patskovsky, Z.Li, R.Toro, A.Meyer, H.Cheng, M.Brenowitz, S.G.Nathenson, and S.C.Almo (2009).
Biochemical and structural characterization of the human TL1A ectodomain.
  Biochemistry, 48, 7636-7645.
PDB codes: 2qe3 2rjk 2rjl
19117685 D.Mahalingam, E.Szegezdi, M.Keane, S.de Jong, and A.Samali (2009).
TRAIL receptor signalling and modulation: Are we on the right TRAIL?
  Cancer Treat Rev, 35, 280-288.  
19426226 G.Cai, and G.J.Freeman (2009).
The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation.
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20046044 K.Iha, T.Omatsu, S.Watanabe, N.Ueda, S.Taniguchi, H.Fujii, Y.Ishii, S.Kyuwa, H.Akashi, and Y.Yoshikawa (2009).
Molecular cloning and sequencing of the cDNAs encoding the bat interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12p40, and tumor necrosis factor-alpha.
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19412666 M.E.Gasparian, B.V.Chernyak, D.A.Dolgikh, A.V.Yagolovich, E.N.Popova, A.M.Sycheva, S.A.Moshkovskii, and M.P.Kirpichnikov (2009).
Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5.
  Apoptosis, 14, 778-787.  
19229339 M.Jeong, Y.S.Kwon, S.H.Park, C.Y.Kim, S.S.Jeun, K.W.Song, Y.Ko, P.D.Robbins, T.R.Billiar, B.M.Kim, and D.W.Seol (2009).
Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.
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19412671 W.Chen, J.Zhang, T.Zhang, H.Li, W.Wang, Z.Xia, and M.Wang (2009).
Improved isolation of anti-rhTNF-alpha scFvs from phage display library by bioinformatics.
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18989337 A.Ashkenazi (2008).
Directing cancer cells to self-destruct with pro-apoptotic receptor agonists.
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18219321 C.Adams, K.Totpal, D.Lawrence, S.Marsters, R.Pitti, S.Yee, S.Ross, L.Deforge, H.Koeppen, M.Sagolla, D.Compaan, H.Lowman, S.Hymowitz, and A.Ashkenazi (2008).
Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5.
  Cell Death Differ, 15, 751-761.  
18474604 V.Tur, A.M.van der Sloot, C.R.Reis, E.Szegezdi, R.H.Cool, A.Samali, L.Serrano, and W.J.Quax (2008).
DR4-selective tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) variants obtained by structure-based design.
  J Biol Chem, 283, 20560-20568.  
17724141 D.Daniel, B.Yang, D.A.Lawrence, K.Totpal, I.Balter, W.P.Lee, A.Gogineni, M.J.Cole, S.F.Yee, S.Ross, and A.Ashkenazi (2007).
Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts.
  Blood, 110, 4037-4046.  
17609857 M.E.Gasparian, V.G.Ostapchenko, A.V.Yagolovich, I.N.Tsygannik, B.V.Chernyak, D.A.Dolgikh, and M.P.Kirpichnikov (2007).
Overexpression and refolding of thioredoxin/TRAIL fusion from inclusion bodies and further purification of TRAIL after cleavage by enteropeptidase.
  Biotechnol Lett, 29, 1567-1573.  
17917057 M.P.Simons, W.M.Nauseef, and T.S.Griffith (2007).
Neutrophils and TRAIL: insights into BCG immunotherapy for bladder cancer.
  Immunol Res, 39, 79-93.  
17256800 P.Tarpey, T.J.Pemberton, D.W.Stockton, P.Das, V.Ninis, S.Edkins, P.Andrew Futreal, R.Wooster, S.Kamath, R.Nayak, M.R.Stratton, and P.I.Patel (2007).
A novel Gln358Glu mutation in ectodysplasin A associated with X-linked dominant incisor hypodontia.
  Am J Med Genet A, 143, 390-394.  
17705261 X.Volkmann, U.Fischer, M.J.Bahr, M.Ott, F.Lehner, M.Macfarlane, G.M.Cohen, M.P.Manns, K.Schulze-Osthoff, and H.Bantel (2007).
Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver.
  Hepatology, 46, 1498-1508.  
17318333 Y.S.Youn, M.J.Shin, S.Y.Chae, C.H.Jin, T.H.Kim, and K.C.Lee (2007).
Biological and physicochemical evaluation of the conformational stability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
  Biotechnol Lett, 29, 713-721.  
16731632 A.M.van der Sloot, V.Tur, E.Szegezdi, M.M.Mullally, R.H.Cool, A.Samali, L.Serrano, and W.J.Quax (2006).
Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor.
  Proc Natl Acad Sci U S A, 103, 8634-8639.  
16799759 A.Y.Sun, Y.L.Shen, J.C.Yin, H.Zhang, Y.N.Tang, and D.Z.Wei (2006).
Improvement of expression level and bioactivity of soluble tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) by a novel zinc ion feeding strategy.
  Biotechnol Lett, 28, 1215-1219.  
16547002 C.Bossen, K.Ingold, A.Tardivel, J.L.Bodmer, O.Gaide, S.Hertig, C.Ambrose, J.Tschopp, and P.Schneider (2006).
Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human.
  J Biol Chem, 281, 13964-13971.  
16195699 C.Y.Kim, M.Jeong, H.Mushiake, B.M.Kim, W.B.Kim, J.P.Ko, M.H.Kim, M.Kim, T.H.Kim, P.D.Robbins, T.R.Billiar, and D.W.Seol (2006).
Cancer gene therapy using a novel secretable trimeric TRAIL.
  Gene Ther, 13, 330-338.  
16966254 F.Corallini, D.Milani, V.Nicolin, and P.Secchiero (2006).
TRAIL, caspases and maturation of normal and leukemic myeloid precursors.
  Leuk Lymphoma, 47, 1459-1468.  
16820090 M.F.Ziauddin, W.S.Yeow, J.B.Maxhimer, A.Baras, A.Chua, R.M.Reddy, W.Tsai, G.W.Cole, D.S.Schrump, and D.M.Nguyen (2006).
Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation.
  Neoplasia, 8, 446-457.  
16888647 P.M.Eimon, E.Kratz, E.Varfolomeev, S.G.Hymowitz, H.Stern, J.Zha, and A.Ashkenazi (2006).
Delineation of the cell-extrinsic apoptosis pathway in the zebrafish.
  Cell Death Differ, 13, 1619-1630.  
15864587 T.J.Sayers, and W.J.Murphy (2006).
Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for cancer therapy.
  Cancer Immunol Immunother, 55, 76-84.  
16772303 T.Murata, M.Tsuboi, K.Hikita, and N.Kaneda (2006).
Protective effects of neurotrophic factors on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of murine adrenal chromaffin cell line tsAM5D.
  J Biol Chem, 281, 22503-22516.  
15505785 C.H.Schein, B.Zhou, N.Oezguen, V.S.Mathura, and W.Braun (2005).
Molego-based definition of the architecture and specificity of metal-binding sites.
  Proteins, 58, 200-210.  
16225761 F.Fang, A.P.Wang, and S.F.Yang (2005).
Antitumor activity of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand.
  Acta Pharmacol Sin, 26, 1373-1381.  
15672328 M.Mita, and A.W.Tolcher (2005).
Novel apoptosis inducing agents in cancer therapy.
  Curr Probl Cancer, 29, 8.  
15651986 P.Marini, A.Schmid, V.Jendrossek, H.Faltin, P.T.Daniel, W.Budach, and C.Belka (2005).
Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis.
  BMC Cancer, 5, 5.  
15290100 Q.L.Fan, W.Y.Zou, L.H.Song, and W.Wei (2005).
Synergistic antitumor activity of TRAIL combined with chemotherapeutic agents in A549 cell lines in vitro and in vivo.
  Cancer Chemother Pharmacol, 55, 189-196.  
15520016 R.F.Kelley, K.Totpal, S.H.Lindstrom, M.Mathieu, K.Billeci, L.Deforge, R.Pai, S.G.Hymowitz, and A.Ashkenazi (2005).
Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling.
  J Biol Chem, 280, 2205-2212.  
15711921 S.Bouralexis, D.M.Findlay, and A.Evdokiou (2005).
Death to the bad guys: targeting cancer via Apo2L/TRAIL.
  Apoptosis, 10, 35-51.  
15226295 S.H.Kim, K.Kim, J.G.Kwagh, D.T.Dicker, M.Herlyn, A.K.Rustgi, Y.Chen, and W.S.El-Deiry (2004).
Death induction by recombinant native TRAIL and its prevention by a caspase 9 inhibitor in primary human esophageal epithelial cells.
  J Biol Chem, 279, 40044-40052.  
15158769 S.Shankar, and R.K.Srivastava (2004).
Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications.
  Drug Resist Updat, 7, 139-156.  
15562003 T.Mori, A.Oguro, T.Ohtsu, and Y.Nakamura (2004).
RNA aptamers selected against the receptor activator of NF-kappaB acquire general affinity to proteins of the tumor necrosis factor receptor family.
  Nucleic Acids Res, 32, 6120-6128.  
15238075 Ã.˜.Halaas, N.B.Liabakk, R.Vik, C.Beninati, P.Henneke, A.Sundan, and T.Espevik (2004).
Monocytes stimulated with group B streptococci or interferons release tumour necrosis factor-related apoptosis-inducing ligand.
  Scand J Immunol, 60, 74-81.  
  12787570 A.Almasan, and A.Ashkenazi (2003).
Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy.
  Cytokine Growth Factor Rev, 14, 337-348.  
  14656435 S.G.Hymowitz, D.M.Compaan, M.Yan, H.J.Wallweber, V.M.Dixit, M.A.Starovasnik, and A.M.de Vos (2003).
The crystal structures of EDA-A1 and EDA-A2: splice variants with distinct receptor specificity.
  Structure, 11, 1513-1520.
PDB code: 1rj8
12189384 A.Ashkenazi (2002).
Targeting death and decoy receptors of the tumour-necrosis factor superfamily.
  Nat Rev Cancer, 2, 420-430.  
11862220 D.A.Oren, Y.Li, Y.Volovik, T.S.Morris, C.Dharia, K.Das, O.Galperina, R.Gentz, and E.Arnold (2002).
Structural basis of BLyS receptor recognition.
  Nat Struct Biol, 9, 288-292.
PDB code: 1kxg
12392561 G.H.Nam, and K.Y.Choi (2002).
Association of human tumor necrosis factor-related apoptosis inducing ligand with membrane upon acidification.
  Eur J Biochem, 269, 5280-5287.  
11796220 J.L.Bodmer, P.Schneider, and J.Tschopp (2002).
The molecular architecture of the TNF superfamily.
  Trends Biochem Sci, 27, 19-26.  
12473065 J.Z.Qin, P.E.Bacon, V.Chaturvedi, B.Bonish, and B.J.Nickoloff (2002).
Pathways involved in proliferating, senescent and immortalized keratinocyte cell death mediated by two different TRAIL preparations.
  Exp Dermatol, 11, 573-583.  
11924906 P.Cappello, F.Novelli, G.Forni, and M.Giovarelli (2002).
Death receptor ligands in tumors.
  J Immunother (1997), 25, 1.  
11733492 S.Ito, K.Wakabayashi, O.Ubukata, S.Hayashi, F.Okada, and T.Hata (2002).
Crystal structure of the extracellular domain of mouse RANK ligand at 2.2-A resolution.
  J Biol Chem, 277, 6631-6636.
PDB code: 1iqa
11507096 H.Higuchi, S.F.Bronk, Y.Takikawa, N.Werneburg, R.Takimoto, W.El-Deiry, and G.J.Gores (2001).
The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis.
  J Biol Chem, 276, 38610-38618.  
11991679 J.Held, and K.Schulze-Osthoff (2001).
Potential and caveats of TRAIL in cancer therapy.
  Drug Resist Updat, 4, 243-252.  
11746948 R.L.Rich, and D.G.Myszka (2001).
Survey of the year 2000 commercial optical biosensor literature.
  J Mol Recognit, 14, 273-294.  
11114500 E.Y.Jones (2000).
The tumour necrosis factor receptor family: life or death choices.
  Curr Opin Struct Biol, 10, 644-648.  
10894161 F.C.Kischkel, D.A.Lawrence, A.Chuntharapai, P.Schow, K.J.Kim, and A.Ashkenazi (2000).
Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5.
  Immunity, 12, 611-620.  
10891884 H.T.Idriss, and J.H.Naismith (2000).
TNF alpha and the TNF receptor superfamily: structure-function relationship(s).
  Microsc Res Tech, 50, 184-195.  
11039935 M.Yan, L.C.Wang, S.G.Hymowitz, S.Schilbach, J.Lee, A.Goddard, A.M.de Vos, W.Q.Gao, and V.M.Dixit (2000).
Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors.
  Science, 290, 523-527.  
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.