PDBsum entry 1jdh

Transcription

PDB id: 1jdh

Contents

Protein chains

508 a.a. *

38 a.a. *

Waters ×393

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Tcf4 can specifically recognize beta-Catenin using alternative conformations.

Authors

T.A.Graham, D.M.Ferkey, F.Mao, D.Kimelman, W.Xu.

Ref.

Nat Struct Biol, 2001, 8, 1048-1052. [DOI no: 10.1038/nsb718]

PubMed id

11713475

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.

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.