PDBsum entry 1jpw

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protein Protein-protein interface(s) links
Cell adhesion PDB id
Protein chains
502 a.a. *
24 a.a. *
Waters ×848
* Residue conservation analysis
PDB id:
Name: Cell adhesion
Title: Crystal structure of a human tcf-4 / beta-catenin complex
Structure: Beta-catenin. Chain: a, b, c. Engineered: yes. Transcription factor 7-like 2. Chain: d, e, f. Synonym: tcf4. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
2.50Å     R-factor:   0.304     R-free:   0.390
Authors: F.Poy,M.Lepourcelet,R.A.Shivdasani,M.J.Eck
Key ref:
F.Poy et al. (2001). Structure of a human Tcf4-beta-catenin complex. Nat Struct Biol, 8, 1053-1057. PubMed id: 11713476 DOI: 10.1038/nsb720
03-Aug-01     Release date:   05-Dec-01    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P35222  (CTNB1_HUMAN) -  Catenin beta-1
781 a.a.
502 a.a.
Protein chains
Pfam   ArchSchema ?
Q9NQB0  (TF7L2_HUMAN) -  Transcription factor 7-like 2
619 a.a.
24 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     Wnt receptor signaling pathway   1 term 


DOI no: 10.1038/nsb720 Nat Struct Biol 8:1053-1057 (2001)
PubMed id: 11713476  
Structure of a human Tcf4-beta-catenin complex.
F.Poy, M.Lepourcelet, R.A.Shivdasani, M.J.Eck.
The multifunctional protein beta-catenin is important for cell adhesion, because it binds cadherins, and the Wnt signal transduction pathway, where it interacts with the Adenomatous polyposis coli (APC) protein and TCF/Lef family transcription factors. Mutations in APC or in beta-catenin are estimated to trigger formation of over 90% of all colon cancers. In colonic epithelia, these mutations produce elevated levels of Tcf4-beta-catenin, which stimulates a transcriptional response that initiates polyp formation and eventually malignant growth. Thus, disruption of the Tcf4-beta-catenin interaction may be an attractive goal for therapeutic intervention. Here we describe the crystal structure of a human Tcf4-beta-catenin complex and compare it with recent structures of beta-catenin in complex with Xenopus Tcf3 (XTcf3) and mammalian E-cadherin. The structure reveals anticipated similarities with the closely related XTcf3 complex but unexpectedly lacks one component observed in the XTcf3 structure.
  Selected figure(s)  
Figure 1.
Figure 1. Structure of the Tcf4 - -catenin complex. a, The Tcf4 peptide (yellow) has two sites of interaction with the armadillo repeat region of -catenin (blue): an 'extended region' composed of residues 13 -25 (labeled N in yellow) and a more C-terminal helical region composed of residues 40 -50 (labeled C in yellow). The intervening 14 residues are disordered, as are residues 8 -12 at the N-terminus and 51 -54 at the C-terminus. b, Detail of interactions in the extended region. Tcf4 residues Asp 16 and Glu 17 form salt bridge hydrogen bonds with -catenin Lys 435 and Lys 508, respectively. For clarity, only a subset of the hydrogen bonds in this region is indicated. c, Detail of interactions in the C-terminal helix. Tcf4 residues Leu 41, Val 44, Leu 48 and Val 49 form the hydrophobic surface of the amphipathic helix. In (b,c), Tcf4 residues are colored yellow and -catenin residues are shown in blue. Thin magenta lines indicate hydrogen bonds; the small red sphere is an ordered water molecule. The figure was prepared with MOLSCRIPT33.
Figure 2.
Figure 2. The Tcf4 extended region binds a positively charged groove. a, Stereo view of the molecular surface of -catenin, colored by electrostatic potential, reveals a positively charged cleft. Acidic residues at either end of the extended portion of Tcf4 form salt bridges with basic residues in -catenin (Fig. 1). Leu 18, Ile 19 and Phe 21 form hydrophobic interactions in the center of the cleft. Electrostatics were calculated with the peptide removed using GRASP34 and are shaded from -10 kT e^-1 (red) to +10 kT e^-1 (blue). b, Stereo view of the 2F[o] - F[c] electron density map corresponding to a segment of Tcf4, calculated with molecular replacement phases prior to inclusion of Tcf4 in the model. The 2.8 map is contoured at 0.8 and shown with the final refined Tcf4 model.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2001, 8, 1053-1057) copyright 2001.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21292023 R.Lu, F.Bian, X.Zhang, H.Qi, E.Y.Chuang, S.C.Pflugfelder, and D.Q.Li (2011).
The β-catenin/Tcf4/survivin signaling maintains a less differentiated phenotype and high proliferative capacity of human corneal epithelial progenitor cells.
  Int J Biochem Cell Biol, 43, 751-759.  
21182262 S.Mokhtarzada, C.Yu, A.Brickenden, and W.Y.Choy (2011).
Structural characterization of partially disordered human chibby: insights into its function in the wnt-signaling pathway.
  Biochemistry, 50, 715-726.  
19966299 G.S.Yochum, C.M.Sherrick, M.Macpartlin, and R.H.Goodman (2010).
A beta-catenin/TCF-coordinated chromatin loop at MYC integrates 5' and 3' Wnt responsive enhancers.
  Proc Natl Acad Sci U S A, 107, 145-150.  
20878273 O.Hansson, Y.Zhou, E.Renström, and P.Osmark (2010).
Molecular function of TCF7L2: Consequences of TCF7L2 splicing for molecular function and risk for type 2 diabetes.
  Curr Diab Rep, 10, 444-451.  
19901072 P.M.Evans, X.Chen, W.Zhang, and C.Liu (2010).
KLF4 interacts with beta-catenin/TCF4 and blocks p300/CBP recruitment by beta-catenin.
  Mol Cell Biol, 30, 372-381.  
18477457 J.Liu, B.T.Phillips, M.F.Amaya, J.Kimble, and W.Xu (2008).
The C. elegans SYS-1 protein is a bona fide beta-catenin.
  Dev Cell, 14, 751-761.
PDB codes: 3c2g 3c2h
18445773 L.Jin, Y.Li, C.J.Chen, M.A.Sherman, K.Le, and J.E.Shively (2008).
Direct interaction of tumor suppressor CEACAM1 with beta catenin: identification of key residues in the long cytoplasmic domain.
  Exp Biol Med (Maywood), 233, 849-859.  
18692117 M.Iiizumi, W.Liu, S.K.Pai, E.Furuta, and K.Watabe (2008).
Drug development against metastasis-related genes and their pathways: a rationale for cancer therapy.
  Biochim Biophys Acta, 1786, 87.  
17875931 D.Sinner, J.J.Kordich, J.R.Spence, R.Opoka, S.Rankin, S.C.Lin, D.Jonatan, A.M.Zorn, and J.M.Wells (2007).
Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells.
  Mol Cell Biol, 27, 7802-7815.  
17961830 M.J.Gorczynski, J.Grembecka, Y.Zhou, Y.Kong, L.Roudaia, M.G.Douvas, M.Newman, I.Bielnicka, G.Baber, T.Corpora, J.Shi, M.Sridharan, R.Lilien, B.R.Donald, N.A.Speck, M.L.Brown, and J.H.Bushweller (2007).
Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta.
  Chem Biol, 14, 1186-1197.  
17660262 M.Ritco-Vonsovici, A.Ababou, and M.Horton (2007).
Molecular plasticity of beta-catenin: new insights from single-molecule measurements and MD simulation.
  Protein Sci, 16, 1984-1998.  
17057340 E.Oksanen, V.P.Jaakola, T.Tolonen, K.Valkonen, B.Akerström, N.Kalkkinen, V.Virtanen, and A.Goldman (2006).
Reindeer beta-lactoglobulin crystal structure with pseudo-body-centred noncrystallographic symmetry.
  Acta Crystallogr D Biol Crystallogr, 62, 1369-1374.
PDB code: 1yup
16824055 F.Tang, Y.Peng, J.J.Nau, E.J.Kauffman, and L.S.Weisman (2006).
Vac8p, an armadillo repeat protein, coordinates vacuole inheritance with multiple vacuolar processes.
  Traffic, 7, 1368-1377.  
16293619 H.J.Choi, A.H.Huber, and W.I.Weis (2006).
Thermodynamics of beta-catenin-ligand interactions: the roles of the N- and C-terminal tails in modulating binding affinity.
  J Biol Chem, 281, 1027-1038.  
17052462 J.Sampietro, C.L.Dahlberg, U.S.Cho, T.R.Hinds, D.Kimelman, and W.Xu (2006).
Crystal structure of a beta-catenin/BCL9/Tcf4 complex.
  Mol Cell, 24, 293-300.
PDB code: 2gl7
16568448 J.Y.Trosset, C.Dalvit, S.Knapp, M.Fasolini, M.Veronesi, S.Mantegani, L.M.Gianellini, C.Catana, M.Sundström, P.F.Stouten, and J.K.Moll (2006).
Inhibition of protein-protein interactions: the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening.
  Proteins, 64, 60-67.  
16683072 N.Janssens, M.Janicot, and T.Perera (2006).
The Wnt-dependent signaling pathways as target in oncology drug discovery.
  Invest New Drugs, 24, 263-280.  
16644723 S.Takayama, I.Rogatsky, L.E.Schwarcz, and B.D.Darimont (2006).
The glucocorticoid receptor represses cyclin D1 by targeting the Tcf-beta-catenin complex.
  J Biol Chem, 281, 17856-17863.  
15768032 D.L.Daniels, and W.I.Weis (2005).
Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation.
  Nat Struct Mol Biol, 12, 364-371.  
15591320 R.Gail, R.Frank, and A.Wittinghofer (2005).
Systematic peptide array-based delineation of the differential beta-catenin interaction with Tcf4, E-cadherin, and adenomatous polyposis coli.
  J Biol Chem, 280, 7107-7117.  
15112230 J.M.Gooding, K.L.Yap, and M.Ikura (2004).
The cadherin-catenin complex as a focal point of cell adhesion and signalling: new insights from three-dimensional structures.
  Bioessays, 26, 497-511.  
15314234 K.H.Emami, C.Nguyen, H.Ma, D.H.Kim, K.W.Jeong, M.Eguchi, R.T.Moon, J.L.Teo, S.W.Oh, H.Y.Kim, S.H.Moon, J.R.Ha, and M.Kahn (2004).
A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected].
  Proc Natl Acad Sci U S A, 101, 12682-12687.  
15060161 L.Lévy, Y.Wei, C.Labalette, Y.Wu, C.A.Renard, M.A.Buendia, and C.Neuveut (2004).
Acetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction.
  Mol Cell Biol, 24, 3404-3414.  
14749129 M.Lepourcelet, Y.N.Chen, D.S.France, H.Wang, P.Crews, F.Petersen, C.Bruseo, A.W.Wood, and R.A.Shivdasani (2004).
Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex.
  Cancer Cell, 5, 91.  
15327769 Y.Xing, W.K.Clements, I.Le Trong, T.R.Hinds, R.Stenkamp, D.Kimelman, and W.Xu (2004).
Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function.
  Mol Cell, 15, 523-533.
PDB code: 1th1
12799378 A.L.Amir, M.Barua, N.C.McKnight, S.Cheng, X.Yuan, and S.P.Balk (2003).
A direct beta-catenin-independent interaction between androgen receptor and T cell factor 4.
  J Biol Chem, 278, 30828-30834.  
12702867 T.Pawson, and P.Nash (2003).
Assembly of cell regulatory systems through protein interaction domains.
  Science, 300, 445-452.  
12006483 A.Hurlstone, and H.Clevers (2002).
T-cell factors: turn-ons and turn-offs.
  EMBO J, 21, 2303-2311.  
11839490 H.J.Dyson, and P.E.Wright (2002).
Coupling of folding and binding for unstructured proteins.
  Curr Opin Struct Biol, 12, 54-60.  
11983149 M.van de Wetering, Lau, and H.Clevers (2002).
WNT signaling and lymphocyte development.
  Cell, 109, S13-S19.  
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.