ICAT inhibits beta-catenin binding to Tcf/Lef-family transcription factors and the general coactivator p300 using independent structural modules

Mol Cell. 2002 Sep;10(3):573-84. doi: 10.1016/s1097-2765(02)00631-7.

Abstract

In the canonical Wnt signaling pathway, beta-catenin activates target genes through its interactions with Tcf/Lef-family transcription factors and additional transcriptional coactivators. The crystal structure of ICAT, an inhibitor of beta-catenin-mediated transcription, bound to the armadillo repeat domain of beta-catenin, has been determined. ICAT contains an N-terminal helilical domain that binds to repeats 11 and 12 of beta-catenin, and an extended C-terminal region that binds to repeats 5-10 in a manner similar to that of Tcfs and other beta-catenin ligands. Full-length ICAT dissociates complexes of beta-catenin, Lef-1, and the transcriptional coactivator p300, whereas the helical domain alone selectively blocks binding to p300. The C-terminal armadillo repeats of beta-catenin may be an attractive target for compounds designed to disrupt aberrant beta-catenin-mediated transcription associated with various cancers.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins*
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • DNA-Binding Proteins / metabolism*
  • E1A-Associated p300 Protein
  • Genes, Reporter
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lymphoid Enhancer-Binding Factor 1
  • Macromolecular Substances
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Muscle Proteins / chemistry
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins*
  • Sequence Alignment
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • beta Catenin

Substances

  • Adaptor Proteins, Signal Transducing
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • CTNNBIP1 protein, human
  • Cell Cycle Proteins
  • Ctnnbip1 protein, mouse
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • LEF1 protein, human
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • Macromolecular Substances
  • Muscle Proteins
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • beta Catenin
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse

Associated data

  • PDB/1I7W
  • PDB/1M1E