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PDBsum entry 1qsc

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protein ligands Protein-protein interface(s) links
Signaling protein PDB id
1qsc
Jmol
Contents
Protein chain
179 a.a. *
Ligands
ACE-TYR-PRO-ILE-
GLN-GLU-THR
×3
Waters ×273
* Residue conservation analysis
PDB id:
1qsc
Name: Signaling protein
Title: Crystal structure of the traf domain of traf2 in a complex with a peptide from the cd40 receptor
Structure: Tnf receptor associated factor 2. Chain: a, b, c. Fragment: traf domain. Synonym: traf2. Engineered: yes. Cd40 receptor. Chain: d, e, f. Fragment: traf binding peptide. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Other_details: sequence derived from human cd40
Biol. unit: Trimer (from PDB file)
Resolution:
2.40Å     R-factor:   0.215     R-free:   0.257
Authors: S.M.Mcwhirter,S.S.Pullen,J.M.Holton,J.J.Crute,M.R.Kehry, T.Alber
Key ref:
S.M.McWhirter et al. (1999). Crystallographic analysis of CD40 recognition and signaling by human TRAF2. Proc Natl Acad Sci U S A, 96, 8408-8413. PubMed id: 10411888 DOI: 10.1073/pnas.96.15.8408
Date:
20-Jun-99     Release date:   01-Aug-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.
179 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     regulation of apoptotic process   5 terms 
  Biochemical function     ubiquitin-protein ligase activity     1 term  

 

 
DOI no: 10.1073/pnas.96.15.8408 Proc Natl Acad Sci U S A 96:8408-8413 (1999)
PubMed id: 10411888  
 
 
Crystallographic analysis of CD40 recognition and signaling by human TRAF2.
S.M.McWhirter, S.S.Pullen, J.M.Holton, J.J.Crute, M.R.Kehry, T.Alber.
 
  ABSTRACT  
 
Tumor necrosis factor receptor superfamily members convey signals that promote diverse cellular responses. Receptor trimerization by extracellular ligands initiates signaling by recruiting members of the tumor necrosis factor receptor-associated factor (TRAF) family of adapter proteins to the receptor cytoplasmic domains. We report the 2.4-A crystal structure of a 22-kDa, receptor-binding fragment of TRAF2 complexed with a functionally defined peptide from the cytoplasmic domain of the CD40 receptor. TRAF2 forms a mushroom-shaped trimer consisting of a coiled coil and a unique beta-sandwich domain. Both domains mediate trimerization. The CD40 peptide binds in an extended conformation with every side chain in contact with a complementary groove on the rim of each TRAF monomer. The spacing between the CD40 binding sites on TRAF2 supports an elegant signaling mechanism in which trimeric, extracellular ligands preorganize the receptors to simultaneously recognize three sites on the TRAF trimer.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Three-dimensional structure of the TRAF-CD40-p1 complex. TRAF2-311 forms a trimer (blue, yellow, and green ribbons), and the CD40-p1 peptides (space-filling; atom colors) bind to the rim of all three TRAF2 monomers. TRAF-N domain sequences form a parallel coiled coil, followed by the TRAF-C domain, which adopts a topologically unique -sandwich. (A) View along the trimer axis with the coiled coil in the front. The side chains of the conserved TrpLysIle motif implicated in recruitment of NF- B inducing kinase, NIK (23), are shown in orange. The CD40 peptides are 38 Å from the trimer axis and 54 Å from each other. (B) Side view with the trimer axis vertical. The helix 2 is on the underside of the C domain, and the C terminus is at the top.
Figure 3.
Fig. 3. Receptor recognition by TRAF2. (A) Refined model of CD40-p1 (Tyr-249-Thr-254) superimposed on the solvent-flattened, MAD-phased, 2.4-Å-resolution electron density map (1 ). (B) Stereo view of the TRAF2-CD40-p1 contacts. The TRAF2 backbone is depicted with ribbons. Side chains of TRAF2 residues positioned to make hydrogen bonds to CD40-p1 are shown in purple. The serine tongs, in which conserved serines 453-455 form hydrogen bonds with CD40 Gln-252, are shown at the upper right. CD40 Glu-253 is at the bottom, within hydrogen-bonding distance of TRAF2 Arg-393 and Tyr-395. CD40 Thr-254 is within hydrogen-bonding distance of the conserved Asp-399. Primes (') denote CD40 residues. (C) CD40-p1 (stick model) shown on the solvent accessible surface of TRAF2 colored by electrostatic potential ( 8 to +8 kT/e; blue, positive; white, neutral; and red, negative). The side chains of CD40 Pro-250 and Ile-251 contact a hydrophobic region of the binding cleft, and the remaining CD40 side chains make polar or charged interactions. (D) Comparison of CD-40-p1 (orange) and TNF-R2 (light blue) bound to TRAF2 (CD40-p1 complex, gray; TNF-R2 complex, blue). Single letters denote the residues in CD40-TNF-R2. Three residues in the TNF-R2 peptide not present in CD40-p1 were omitted. The TRAF2 C domains in the two complexes were superimposed without reference to the receptor peptides. TRAF2 adopts similar conformations in the two complexes. The two receptor sequences make distinct side-chain contacts.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20382987 H.Walden (2010).
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Unleashing cell death: the Fas-FADD complex.
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20133937 S.K.Manna, B.Babajan, P.B.Raghavendra, N.Raviprakash, and C.Sureshkumar (2010).
Inhibiting TRAF2-mediated activation of NF-kappaB facilitates induction of AP-1.
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19228877 H.H.Jabara, Y.Weng, T.Sannikova, and R.S.Geha (2009).
TRAF2 and TRAF3 independently mediate Ig class switching driven by CD40.
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19810754 Q.Yin, B.Lamothe, B.G.Darnay, and H.Wu (2009).
Structural basis for the lack of E2 interaction in the RING domain of TRAF2.
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PDB code: 3knv
19465916 Q.Yin, S.C.Lin, B.Lamothe, M.Lu, Y.C.Lo, G.Hura, L.Zheng, R.L.Rich, A.D.Campos, D.G.Myszka, M.J.Lenardo, B.G.Darnay, and H.Wu (2009).
E2 interaction and dimerization in the crystal structure of TRAF6.
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PDB codes: 3hcs 3hct 3hcu
19426221 R.Elgueta, M.J.Benson, V.C.de Vries, A.Wasiuk, Y.Guo, and R.J.Noelle (2009).
Molecular mechanism and function of CD40/CD40L engagement in the immune system.
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Roles of TRAF6 in CD40 signaling.
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Production of selenomethionyl-derivatized proteins in baculovirus-infected insect cells.
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16646632 E.R.Sprague, C.Wang, D.Baker, and P.J.Bjorkman (2006).
Crystal structure of the HSV-1 Fc receptor bound to Fc reveals a mechanism for antibody bipolar bridging.
  PLoS Biol, 4, e148.
PDB codes: 2giy 2gj7
16291650 J.H.Thomas (2006).
Analysis of homologous gene clusters in Caenorhabditis elegans reveals striking regional cluster domains.
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16825662 J.H.Thomas (2006).
Adaptive evolution in two large families of ubiquitin-ligase adapters in nematodes and plants.
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16972256 K.H.Szymczyk, T.A.Freeman, C.S.Adams, V.Srinivas, and M.J.Steinbeck (2006).
Active caspase-3 is required for osteoclast differentiation.
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Structure of the calcium-rich signature domain of human thrombospondin-2.
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PDB code: 1yo8
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Away from the edge II: in-house Se-SAS phasing with chromium radiation.
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PDB code: 1xho
15708970 J.Hauer, S.Püschner, P.Ramakrishnan, U.Simon, M.Bongers, C.Federle, and H.Engelmann (2005).
TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs.
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16234979 K.Kanazawa, and A.Kudo (2005).
Self-assembled RANK induces osteoclastogenesis ligand-independently.
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16211505 P.D.Laible, A.N.Hata, A.E.Crawford, and D.K.Hanson (2005).
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PDB codes: 1yy6 1yze
15459669 G.A.Bishop (2004).
The multifaceted roles of TRAFs in the regulation of B-cell function.
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14752198 J.Holton, and T.Alber (2004).
Automated protein crystal structure determination using ELVES.
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TRUSS, a novel tumor necrosis factor receptor 1 scaffolding protein that mediates activation of the transcription factor NF-kappaB.
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Downstream regulator TANK binds to the CD40 recognition site on TRAF3.
  Structure, 10, 403-411.
PDB codes: 1kzz 1l0a
12136149 C.Z.Ni, K.Welsh, J.Zheng, M.Havert, J.C.Reed, and K.R.Ely (2002).
Crystallization and preliminary X-ray analysis of the TRAF domain of TRAF3.
  Acta Crystallogr D Biol Crystallogr, 58, 1340-1342.  
11742346 G.Polekhina, C.M.House, N.Traficante, J.P.Mackay, F.Relaix, D.A.Sassoon, M.W.Parker, and D.D.Bowtell (2002).
Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling.
  Nat Struct Biol, 9, 68-75.
PDB code: 1k2f
12354113 H.Glauner, D.Siegmund, H.Motejadded, P.Scheurich, F.Henkler, O.Janssen, and H.Wajant (2002).
Intracellular localization and transcriptional regulation of tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4).
  Eur J Biochem, 269, 4819-4829.  
12140561 H.Ye, J.R.Arron, B.Lamothe, M.Cirilli, T.Kobayashi, N.K.Shevde, D.Segal, O.K.Dzivenu, M.Vologodskaia, M.Yim, K.Du, S.Singh, J.W.Pike, B.G.Darnay, Y.Choi, and H.Wu (2002).
Distinct molecular mechanism for initiating TRAF6 signalling.
  Nature, 418, 443-447.
PDB codes: 1lb4 1lb5 1lb6
11753426 J.C.Reed, and K.R.Ely (2002).
Degrading liaisons: Siah structure revealed.
  Nat Struct Biol, 9, 8.  
12370254 J.R.Arron, Y.Pewzner-Jung, M.C.Walsh, T.Kobayashi, and Y.Choi (2002).
Regulation of the subcellular localization of tumor necrosis factor receptor-associated factor (TRAF)2 by TRAF1 reveals mechanisms of TRAF2 signaling.
  J Exp Med, 196, 923-934.  
12447905 K.R.Ely, and C.Li (2002).
Structurally adaptive hot spots at a protein interaction interface on TRAF3.
  J Mol Recognit, 15, 286-290.  
11856825 O.V.Moroz, A.A.Antson, E.J.Dodson, H.J.Burrell, S.J.Grist, R.M.Lloyd, N.J.Maitland, G.G.Dodson, K.S.Wilson, E.Lukanidin, and I.B.Bronstein (2002).
The structure of S100A12 in a hexameric form and its proposed role in receptor signalling.
  Acta Crystallogr D Biol Crystallogr, 58, 407-413.
PDB code: 1gqm
11387199 A.Kaykas, K.Worringer, and B.Sugden (2001).
CD40 and LMP-1 both signal from lipid rafts but LMP-1 assembles a distinct, more efficient signaling complex.
  EMBO J, 20, 2641-2654.  
11178122 E.M.Gravallese, D.L.Galson, S.R.Goldring, and P.E.Auron (2001).
The role of TNF-receptor family members and other TRAF-dependent receptors in bone resorption.
  Arthritis Res, 3, 6.  
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.  
10891490 A.G.Eliopoulos, C.Davies, P.G.Knox, N.J.Gallagher, S.C.Afford, D.H.Adams, and L.S.Young (2000).
CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily.
  Mol Cell Biol, 20, 5503-5515.  
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.  
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.  
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.  
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.  
10748240 R.Schwandner, K.Yamaguchi, and Z.Cao (2000).
Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction.
  J Exp Med, 191, 1233-1240.  
10856699 U.Schönbeck, F.Mach, and P.Libby (2000).
CD154 (CD40 ligand).
  Int J Biochem Cell Biol, 32, 687-693.  
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
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.  
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.  
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 code is shown on the right.