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Tnf signaling PDB id
1ca4
Jmol
Contents
Protein chains
(+ 0 more) 168 a.a. *
Waters ×743
* Residue conservation analysis
PDB id:
1ca4
Name: Tnf signaling
Title: Structure of tnf receptor associated factor 2 (traf2)
Structure: Protein (tnf receptor associated factor 2). Chain: a, b, c, d, e, f. Fragment: traf domain. Synonym: traf2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Biol. unit: Trimer (from PDB file)
Resolution:
2.20Å     R-factor:   0.209     R-free:   0.251
Authors: Y.C.Park,V.Burkitt,A.R.Villa,L.Tong,H.Wu
Key ref:
Y.C.Park et al. (1999). Structural basis for self-association and receptor recognition of human TRAF2. Nature, 398, 533-538. PubMed id: 10206649 DOI: 10.1038/19110
Date:
23-Feb-99     Release date:   12-Apr-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q12933  (TRAF2_HUMAN) -  TNF receptor-associated factor 2
Seq:
Struc: 		501 a.a.
168 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1038/19110 Nature 398:533-538 (1999)
PubMed id: 10206649  
 
 
Structural basis for self-association and receptor recognition of human TRAF2.
Y.C.Park, V.Burkitt, A.R.Villa, L.Tong, H.Wu.
 
  ABSTRACT  
 
Tumour necrosis factor (TNF)-receptor-associated factors (TRAFs) form a family of cytoplasmic adapter proteins that mediate signal transduction from many members of the TNF-receptor superfamily and the interleukin-1 receptor. They are important in the regulation of cell survival and cell death. The carboxy-terminal region of TRAFs (the TRAF domain) is required for self-association and interaction with receptors. The domain contains a predicted coiled-coil region that is followed by a highly conserved TRAF-C domain. Here we report the crystal structure of the TRAF domain of human TRAF2, both alone and in complex with a peptide from TNF receptor-2 (TNF-R2). The structures reveal a trimeric self-association of the TRAF domain, which we confirm by studies in solution. The TRAF-C domain forms a new, eight-stranded antiparallel beta-sandwich structure. The TNF-R2 peptide binds to a conserved shallow surface depression on one TRAF-C domain and does not contact the other protomers of the trimer. The nature of the interaction indicates that an SXXE motif may be a TRAF2-binding consensus sequence. The trimeric structure of the TRAF domain provides an avidity-based explanation for the dependence of TRAF recruitment on the oligomerization of the receptors by their trimeric extracellular ligands.
 
  Selected figure(s)  
 
Figure 1.
Figure 1: Structure of the TRAF domain alone and in complex with the TNF-R2 peptide. a, Stereo ribbon diagram of the TRAF domain of human TRAF2 in the peptide-free structure. The -strands, -helices and loops are shown in cyan, yellow and purple, respectively. The loop between 7 and 8 is highly flexible andexhibits a different conformation in the peptide-bound structure b, Ribbon drawing of the trimeric TRAF domain in complex with TNF-R2 peptide, looking down the three-fold axis. The -strands in each protomer are shown in cyan, green and dark blue. The peptide is shown as a stick model for the protomer incyan. Residues of the TRAF-C domain in the trimer interface (between the protomers shown in cyan and dark blue) are also shown as stick models. The TRAF-C domain of the structure obeys proper three-fold symmetry, whereas the coiled-coil domain shows significant deviations. c, As for b, except that the three-fold axis is now vertical. 		Figure 3.
Figure 3: Detailed interaction between TRAF2 and the TNF-R2 peptide. a,Simulated annealing omit difference map for the TNF-R2 peptide calculated with reflections between 20.0 and 2.3 Å resolution and contoured at 2.0 . The peptide model is superimposed. b, Molecular surface of a TRAF2 promoter, showing the bound TNF-R2 peptide as a stick model; the three-fold axis is in the vertical orientation. Surface colour coding is according to electrostatic surface potential, scaled from -30 to +30 kTe^-1, with blue for positive and red for negative. Selected residues in the receptor peptide and the underlying secondary-structural elements of TRAF2 at the binding site are labelled. c, Stereo view of the detailed interaction between the TNF-R2 peptide (carbon atoms shown in yellow) and the TRAF2 protomer (carbon atoms shown in grey). The main chain of the TRAF2 structure is shown in cyan as backbone worms. Selected residues in the peptide (primed numbers in green) and the protein (in grey) are labelled. Hydrogen bonds and a salt bridge are shown as black dotted lines.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1999, 398, 533-538) copyright 1999.  
  Figures were selected by an automated process.  

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PDB codes: 1lb4 1lb5 1lb6
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Structurally adaptive hot spots at a protein interaction interface on TRAF3.
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  Acta Crystallogr D Biol Crystallogr, 58, 407-413.
PDB code: 1gqm
11777919 P.Xia, L.Wang, P.A.Moretti, N.Albanese, F.Chai, S.M.Pitson, R.J.D'Andrea, J.R.Gamble, and M.A.Vadas (2002).
Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling.
  J Biol Chem, 277, 7996-8003.  
12023963 Y.C.Xu, R.F.Wu, Y.Gu, Y.S.Yang, M.C.Yang, F.E.Nwariaku, and L.S.Terada (2002).
Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase.
  J Biol Chem, 277, 28051-28057.  
11313471 E.C.Wang, A.Thern, A.Denzel, J.Kitson, S.N.Farrow, and M.J.Owen (2001).
DR3 regulates negative selection during thymocyte development.
  Mol Cell Biol, 21, 3451-3461.  
  11167129 H.Wajant, and P.Scheurich (2001).
Tumor necrosis factor receptor-associated factor (TRAF) 2 and its role in TNF signaling.
  Int J Biochem Cell Biol, 33, 19-32.  
11384740 J.Moscat, L.Sanz, P.Sanchez, and M.T.Diaz-Meco (2001).
Regulation and role of the atypical PKC isoforms in cell survival during tumor transformation.
  Adv Enzyme Regul, 41, 99.  
11676830 J.Z.Qin, P.Bacon, V.Chaturvedi, and B.J.Nickoloff (2001).
Role of NF-kappaB activity in apoptotic response of keratinocytes mediated by interferon-gamma, tumor necrosis factor-alpha, and tumor-necrosis-factor-related apoptosis-inducing ligand.
  J Invest Dermatol, 117, 898-907.  
11250893 N.Kobayashi, Y.Kadono, A.Naito, K.Matsumoto, T.Yamamoto, S.Tanaka, and J.Inoue (2001).
Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis.
  EMBO J, 20, 1271-1280.  
11239407 R.M.Locksley, N.Killeen, and M.J.Lenardo (2001).
The TNF and TNF receptor superfamilies: integrating mammalian biology.
  Cell, 104, 487-501.  
11514191 V.Baud, and M.Karin (2001).
Signal transduction by tumor necrosis factor and its relatives.
  Trends Cell Biol, 11, 372-377.  
  11257231 Y.Huang, Y.C.Park, R.L.Rich, D.Segal, D.G.Myszka, and H.Wu (2001).
Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain.
  Cell, 104, 781-790.
PDB code: 1i4o
10984535 C.Z.Ni, K.Welsh, E.Leo, C.K.Chiou, H.Wu, J.C.Reed, and K.R.Ely (2000).
Molecular basis for CD40 signaling mediated by TRAF3.
  Proc Natl Acad Sci U S A, 97, 10395-10399.
PDB codes: 1flk 1fll
10911999 D.H.Tsao, T.McDonagh, J.B.Telliez, S.Hsu, K.Malakian, G.Y.Xu, and L.L.Lin (2000).
Solution structure of N-TRADD and characterization of the interaction of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway.
  Mol Cell, 5, 1051-1057.
PDB code: 1f2h
11114500 E.Y.Jones (2000).
The tumour necrosis factor receptor family: life or death choices.
  Curr Opin Struct Biol, 10, 644-648.  
10650002 F.Urano, X.Wang, A.Bertolotti, Y.Zhang, P.Chung, H.P.Harding, and D.Ron (2000).
Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1.
  Science, 287, 664-666.  
10644711 H.Dadgostar, and G.Cheng (2000).
Membrane localization of TRAF 3 enables JNK activation.
  J Biol Chem, 275, 2539-2544.  
10688666 H.Liu, H.Nishitoh, H.Ichijo, and J.M.Kyriakis (2000).
Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin.
  Mol Cell Biol, 20, 2198-2208.  
10908665 H.Ye, and H.Wu (2000).
Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry.
  Proc Natl Acad Sci U S A, 97, 8961-8966.  
10766844 J.M.Zapata, S.Matsuzawa, A.Godzik, E.Leo, S.A.Wasserman, and J.C.Reed (2000).
The Drosophila tumor necrosis factor receptor-associated factor-1 (DTRAF1) interacts with Pelle and regulates NFkappaB activity.
  J Biol Chem, 275, 12102-12107.  
10747026 L.Sanz, M.T.Diaz-Meco, H.Nakano, and J.Moscat (2000).
The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway.
  EMBO J, 19, 1576-1586.  
10753817 M.C.Deller, and E.Yvonne Jones (2000).
Cell surface receptors.
  Curr Opin Struct Biol, 10, 213-219.  
10837071 M.Karin, and Y.Ben-Neriah (2000).
Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.
  Annu Rev Immunol, 18, 621-663.  
10950109 M.L.Gaeta, D.R.Johnson, M.S.Kluger, and J.S.Pober (2000).
The death domain of tumor necrosis factor receptor 1 is necessary but not sufficient for Golgi retention of the receptor and mediates receptor desensitization.
  Lab Invest, 80, 1185-1194.  
10753918 W.R.Force, A.A.Glass, C.A.Benedict, T.C.Cheung, J.Lama, and C.F.Ware (2000).
Discrete signaling regions in the lymphotoxin-beta receptor for tumor necrosis factor receptor-associated factor binding, subcellular localization, and activation of cell death and NF-kappaB pathways.
  J Biol Chem, 275, 11121-11129.  
10892748 Y.C.Park, H.Ye, C.Hsia, D.Segal, R.L.Rich, H.C.Liou, D.G.Myszka, and H.Wu (2000).
A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction.
  Cell, 101, 777-787.
PDB code: 1f3v
10726774 Y.Kuramitsu, M.Fujimoto, T.Tanaka, J.Ohata, and K.Nakamura (2000).
Differential expression of phosphatidylethanol-amine-binding protein in rat hepatoma cell lines: analyses of tumor necrosis factor-alpha-resistant cKDH-8/11 and -sensitive KDH-8/YK cells by two-dimensional gel electrophoresis.
  Electrophoresis, 21, 660-664.  
10428814 E.Leo, K.Welsh, S.Matsuzawa, J.M.Zapata, S.Kitada, R.S.Mitchell, K.R.Ely, and J.C.Reed (1999).
Differential requirements for tumor necrosis factor receptor-associated factor family proteins in CD40-mediated induction of NF-kappaB and Jun N-terminal kinase activation.
  J Biol Chem, 274, 22414-22422.  
10518213 H.Ye, Y.C.Park, M.Kreishman, E.Kieff, and H.Wu (1999).
The structural basis for the recognition of diverse receptor sequences by TRAF2.
  Mol Cell, 4, 321-330.
PDB codes: 1czy 1czz 1d00 1d01 1d0a 1d0j
10549288 S.G.Hymowitz, H.W.Christinger, G.Fuh, M.Ultsch, M.O'Connell, R.F.Kelley, A.Ashkenazi, and A.M.de Vos (1999).
Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5.
  Mol Cell, 4, 563-571.
PDB code: 1d0g
11232332 S.M.McWhirter, S.S.Pullen, B.G.Werneburg, M.E.Labadia, R.H.Ingraham, J.J.Crute, M.R.Kehry, and T.Alber (1999).
Structural and biochemical analysis of signal transduction by the TRAF family of adapter proteins.
  Cold Spring Harb Symp Quant Biol, 64, 551-562.  
10411888 S.M.McWhirter, S.S.Pullen, J.M.Holton, J.J.Crute, M.R.Kehry, and T.Alber (1999).
Crystallographic analysis of CD40 recognition and signaling by human TRAF2.
  Proc Natl Acad Sci U S A, 96, 8408-8413.
PDB code: 1qsc
10433725 S.S.Pullen, M.E.Labadia, R.H.Ingraham, S.M.McWhirter, D.S.Everdeen, T.Alber, J.J.Crute, and M.R.Kehry (1999).
High-affinity interactions of tumor necrosis factor receptor-associated factors (TRAFs) and CD40 require TRAF trimerization and CD40 multimerization.
  Biochemistry, 38, 10168-10177.  
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