Hot spots in beta-catenin for interactions with LEF-1, conductin and APC

Nat Struct Biol. 2000 Sep;7(9):800-7. doi: 10.1038/79039.

Abstract

Interactions between beta-catenin and LEF-1/TCF, APC and conductin/axin are essential for wnt-controlled stabilization of beta-catenin and transcriptional activation. The wnt signal transduction pathway is important in both embryonic development and tumor progression. We identify here amino acid residues in beta-catenin that distinctly affect its binding to LEF-1/TCF, APC and conductin. These residues form separate surface clusters, termed hot spots, along the armadillo superhelix of beta-catenin. We also show that complementary charged and hydrophobic amino acids are required for formation of the bipartite beta-catenin-LEF-1 transcription factor. Moreover, we demonstrate that conductin/axin binding to beta-catenin is essential for beta-catenin degradation, and that APC acts as a cofactor of conductin/axin in this process. Binding of APC to conductin/axin activates the latter and occurs between their SAMP and RGS domains, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein
  • Amino Acid Sequence
  • Animals
  • Axin Protein
  • Binding Sites
  • Cell Line
  • Conserved Sequence
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / chemistry*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Cytoskeletal Proteins / pharmacology
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dogs
  • Humans
  • Ligands
  • Lymphoid Enhancer-Binding Factor 1
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / pharmacology
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Trans-Activators*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Transfection
  • Two-Hybrid System Techniques
  • beta Catenin

Substances

  • AXIN2 protein, human
  • Adenomatous Polyposis Coli Protein
  • Axin Protein
  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • LEF1 protein, human
  • Ligands
  • Lymphoid Enhancer-Binding Factor 1
  • Neoplasm Proteins
  • Trans-Activators
  • Transcription Factors
  • beta Catenin