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PDBsum entry 1jdh
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protein Protein-protein interface(s) links
Transcription PDB id
1jdh

 

 

 

 

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Contents
Protein chains
508 a.a. *
38 a.a. *
Waters ×393
* Residue conservation analysis
PDB id:
1jdh
Name: Transcription
Title: Crystal structure of beta-catenin and htcf-4
Structure: Beta-catenin. Chain: a. Fragment: residues 135-663. Engineered: yes. Htcf-4. Chain: b. Fragment: residues 12-49. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
1.90Å     R-factor:   0.203     R-free:   0.231
Authors: T.A.Graham,D.M.Ferkey,F.Mao,D.Kimelman,W.Xu
Key ref:
T.A.Graham et al. (2001). Tcf4 can specifically recognize beta-catenin using alternative conformations. Nat Struct Biol, 8, 1048-1052. PubMed id: 11713475 DOI: 10.1038/nsb718
Date:
13-Jun-01     Release date:   05-Dec-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P35222  (CTNB1_HUMAN) -  Catenin beta-1 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		781 a.a.
508 a.a.
Protein chain
Pfam   ArchSchema ?
Q9NQB0  (TF7L2_HUMAN) -  Transcription factor 7-like 2 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		619 a.a.
38 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.?
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1038/nsb718 Nat Struct Biol 8:1048-1052 (2001)
PubMed id: 11713475  
 
 
Tcf4 can specifically recognize beta-catenin using alternative conformations.
T.A.Graham, D.M.Ferkey, F.Mao, D.Kimelman, W.Xu.
 
  ABSTRACT  
 
Accumulation of the Wnt pathway effector beta-catenin is a hallmark of a number of cancers, including colon cancer. As beta-catenin accumulates in the cell, it forms a complex with Tcf family transcription factors and activates the transcription of several critical genes involved in cell proliferation. Because Tcf4 is the predominant Tcf factor present in colon cancer cells, drugs that specifically disrupt the beta-catenin-Tcf4 complex could be useful in treating colon cancers. Earlier structural and biochemical studies demonstrated that the central region of the beta-catenin binding domain of Tcf is essential for anchoring Tcf to beta-catenin via two conserved lysines in beta-catenin (called the charged 'buttons'). Here we report the crystal structure of a beta-catenin-Tcf4 complex at 2.0 A resolution. Our structural and mutagenesis studies show that Tcf4 docks specifically to beta-catenin using several distinct conformations in its essential central region. These conformations allow different glutamate residues in the central region of Tcf4 to form a salt bridge with the same critical charged button, Lys 312 of beta-catenin. We propose that this interaction may be the first event in beta-catenin-Tcf4 recognition.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Overall structure of the hTcf4-CBD - -catenin armadillo repeat complex. a, Two views of the -catenin -hTcf4-CBD complex, rotated about the superhelical axis of -catenin by 180°. The -catenin armadillo repeat region is made up of 12 repeats, each consisting of three helices, except for repeat 7, which is made up of only the second and third helices. The three helices for each repeat are denoted in blue, green and yellow, with the yellow helices forming the platform upon which the hTcf4-CBD (red) sits. The hTcf4-CBD lies along the platform of -catenin in an antiparallel fashion with respect to the N- and C-termini of -catenin. The hTcf4 structure presented here consists of three discrete modules (from the N-terminus to the C-terminus): a -strand, a region that contains the kinked -helix and another extended segment followed by the C-terminal -helix. The N-terminus of the hTcf4 in this structure is disordered, as denoted by dashed lines. This figure was generated by MOLSCRIPT25 and RASTER3D^26. b, Sequence alignment of hTcf4-CBD and the XTcf3-CBD, with the structure of each Tcf shown in red. Three critical contacts have been colored, with two of these (turquoise) conserved in the hTcf4-CBD and XTcf3-CBD structure: Asp 16, which binds the first charged button of -catenin, and Leu 48. The third contact occurs between the second charged button of -catenin and a Glu in a conserved acidic cluster of Tcf family members. The Glu in the structure reported here and that reported for the XTcf3-CBD^15 is yellow, and the other Glu residues are green. 		Figure 2.
Figure 2. Comparison of the structural conformations of hTcf4 and XTcf3 near the second charged button (Lys 312). Stick models of the central region of the a, hTcf4-CBD and b, XTcf3-CBD on top of the -catenin molecular surface, which has been shaded to denote the basic (blue) and acidic (red) regions. The Tcf Glu residues are color-coded as in Fig. 1b. This figure was generated by GRASP27. c, Bonding diagram of the hTcf4-CBD kinked helical region. The hTcf4 residues are shown in black; -catenin residues, in red. Hydrophobic interactions are denoted by a red starburst, and hydrogen bonds and charged interactions are denoted in green. Solvent molecules are shown in turquoise. d, Stereo 2F[o] - F[c] omit map of hTcf4-CBD. The hTcf4 residues are denoted in yellow; the -catenin residues, in red. The map is contoured at 1 .
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2001, 8, 1048-1052) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21383188 M.L.Angus-Hill, K.M.Elbert, J.Hidalgo, and M.R.Capecchi (2011).
T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesis.
  Proc Natl Acad Sci U S A, 108, 4914-4919.  
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.  
18682750 I.M.Somorjai, and A.Martinez-Arias (2008).
Wingless signalling alters the levels, subcellular distribution and dynamics of Armadillo and E-cadherin in third instar larval wing imaginal discs.
  PLoS ONE, 3, e2893.  
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
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.  
18054235 P.Tompa, and M.Fuxreiter (2008).
Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions.
  Trends Biochem Sci, 33, 2-8.  
17447011 B.Baminger, M.L.Ludwiczek, G.Kontaxis, S.Knapp, and R.Konrat (2007).
Protein-protein interaction site mapping using NMR-detected mutational scanning.
  J Biomol NMR, 38, 133-137.  
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.  
17452986 Y.Suryo Rahmanto, L.L.Dunn, and D.R.Richardson (2007).
The melanoma tumor antigen, melanotransferrin (p97): a 25-year hallmark--from iron metabolism to tumorigenesis.
  Oncogene, 26, 6113-6124.  
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
17143293 L.Arce, N.N.Yokoyama, and M.L.Waterman (2006).
Diversity of LEF/TCF action in development and disease.
  Oncogene, 25, 7492-7504.  
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.  
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.  
15738986 H.J.Dyson, and P.E.Wright (2005).
Intrinsically unstructured proteins and their functions.
  Nat Rev Mol Cell Biol, 6, 197-208.  
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.  
15554942 A.Schambony, M.Kunz, and D.Gradl (2004).
Cross-regulation of Wnt signaling and cell adhesion.
  Differentiation, 72, 307-318.  
15040893 D.H.Zhao, J.J.Hong, S.Y.Guo, R.L.Yang, J.Yuan, C.Y.Wen, K.Y.Zhou, and C.J.Li (2004).
Aberrant expression and function of TCF4 in the proliferation of hepatocellular carcinoma cell line BEL-7402.
  Cell Res, 14, 74-80.  
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
12657632 M.Fasolini, X.Wu, M.Flocco, J.Y.Trosset, U.Oppermann, and S.Knapp (2003).
Hot spots in Tcf4 for the interaction with beta-catenin.
  J Biol Chem, 278, 21092-21098.  
14600025 Y.Xing, W.K.Clements, D.Kimelman, and W.Xu (2003).
Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta-catenin destruction complex.
  Genes Dev, 17, 2753-2764.
PDB code: 1qz7
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, W.de 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.

 

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