FC0004
T-cell factor 4 (Tcf4) catenin binding domain  -  β-catenin

Biological function
Binding of Tcf family transcription factors to β-catenin activates critical genes for cell proliferation.

Structural evidence
Two electrostatic interactions, established with K312 and K415 in β-catenin (charged buttons) anchors Tcf to its partner. The linking acidic segment (Asp23-Glu-Gly-Glu-Gln-Glu-Glu29), which is conserved in Tcf3 and Tcf4 adopts entirely different conformations in the two proteins upon binding to β-catenin.

Biochemical evidence
Two electrostatic interactions, established with K312 and K415 in β-catenin (charged buttons) anchors Tcf to its partner. The linking acidic segment (Asp23-Glu-Gly-Glu-Gln-Glu-Glu29), which is conserved in Tcf3 and Tcf4 adopts entirely different conformations in the two proteins upon binding to β-catenin.

Structure/Mechanism
Lys-312 in β-catenin likely interacts with Glu 24 or Glu 29 and the additional negatively charged residues either establish buttressing interactions with Lys345, which is also disordered in the complex.

Mechanism category
entropy modulation

Significance
Multiple conformations of the same Tcf is proposed to lower the entropic penalty of binding.

Medical relevance
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 β-catenin−Tcf4 complex could be useful in treating colon cancers.