Structural basis of beta-catenin recognition by Tax-interacting protein-1.

Tax-interacting protein-1 (TIP-1) is an unusual signaling protein, containing a single PDZ domain. TIP-1 is able to bind beta-catenin with high affinity and thus inhibit its transcriptional activity. The high-resolution crystal structure of TIP-1 in complex with the C-terminal peptide of beta-catenin provides molecular details for the recognition of beta-catenin ...
by TIP-1. Moreover, structural comparison of peptide-free and peptide-bound TIP-1 reveals that significant conformational changes are required in the betaB-betaC loop region of TIP-1 to avoid clashes with the incoming C-terminal beta-catenin peptide. Such conformational changes have not been observed in other structures of PDZ domains. In addition to the canonical peptide-binding pocket of the PDZ domain, TIP-1 can form a binding cavity to anchor more amino acids through a conserved hydrophobic residue pair (Trp776 of beta-catenin and Pro45 of TIP-1). Structural and biochemical data indicate that the canonical binding pocket together with the hydrophobic residue pair are presumably the major cause of the significantly higher affinity of the beta-catenin C-terminal to TIP-1 than to other PDZ domains, providing a unique binding specificity. Our results reveal the molecular mechanism of TIP-1 as an antagonist in PDZ domain signaling.
Mesh Terms:
Amino Acid Sequence, Animals, Crystallography, X-Ray, Hydrophobic and Hydrophilic Interactions, Intracellular Signaling Peptides and Proteins, Mice, Models, Molecular, Molecular Sequence Data, Neoplasm Proteins, Peptides, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, beta Catenin
J. Mol. Biol.
Date: Dec. 05, 2008
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