Crystal Structure of a beta-catenin/BCL9/Tcf4 Complex

Mol Cell. 2006 Oct 20;24(2):293-300. doi: 10.1016/j.molcel.2006.09.001.

Abstract

The canonical Wnt pathway plays critical roles in embryonic development, stem cell growth, and tumorigenesis. Stimulation of the Wnt pathway leads to the association of beta-catenin with Tcf and BCL9 in the nucleus, resulting in the transactivation of Wnt target genes. We have determined the crystal structure of a beta-catenin/BCL9/Tcf-4 triple complex at 2.6 A resolution. Our studies reveal that the beta-catenin binding site of BCL9 is distinct from that of most other beta-catenin partners and forms a good target for developing drugs that block canonical Wnt/beta-catenin signaling. The BCL9 beta-catenin binding domain (CBD) forms an alpha helix that binds to the first armadillo repeat of beta-catenin, which can be mutated to prevent beta-catenin binding to BCL9 without affecting cadherin or alpha-catenin binding. We also demonstrate that beta-catenin Y142 phosphorylation, which has been proposed to regulate BCL9-2 binding, does not directly affect the interaction of beta-catenin with either BCL9 or BCL9-2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Humans
  • Kinetics
  • Mice
  • Molecular Conformation
  • Molecular Sequence Data
  • Neoplasm Proteins / chemistry*
  • Protein Conformation
  • TCF Transcription Factors / chemistry*
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • Transcriptional Activation
  • Xenopus
  • Xenopus Proteins
  • alpha Catenin / chemistry
  • beta Catenin / chemistry*

Substances

  • BCL9 protein, human
  • Neoplasm Proteins
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Tcf7l2 protein, mouse
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • Xenopus Proteins
  • alpha Catenin
  • beta Catenin
  • tcf7l2 protein, Xenopus

Associated data

  • PDB/2GL7