Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function.
The tumor suppressor adenomatous polyposis coli (APC) plays a critical role in the turnover of cytosolic beta-catenin, the key effector of the canonical Wnt signaling pathway. APC contains seven 20 amino acid (20 aa) beta-catenin binding repeats that are required for beta-catenin turnover. We have determined the crystal structure of ... beta-catenin in complex with a phosphorylated APC fragment containing two 20 aa repeats. Surprisingly, one single phosphorylated 20 aa repeat, together with its flanking regions, covers the entire structural groove of beta-catenin and may thus compete for beta-catenin binding with all other beta-catenin armadillo repeat partners. Our biochemical studies show that phosphorylation of the APC 20 aa repeats increases the affinity of the repeats for beta-catenin by 300- to 500-fold and the phosphorylated 20 aa repeats prevent beta-catenin binding to Tcf. Our work suggests that the phosphorylation of the APC 20 aa repeats could be a critical switch for APC function.
Mesh Terms:
Adenomatous Polyposis Coli Protein, Amino Acid Sequence, Crystallography, X-Ray, Cytoskeletal Proteins, Humans, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Repetitive Sequences, Nucleic Acid, Sequence Alignment, Trans-Activators, Transcription Factors, beta Catenin
Adenomatous Polyposis Coli Protein, Amino Acid Sequence, Crystallography, X-Ray, Cytoskeletal Proteins, Humans, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Repetitive Sequences, Nucleic Acid, Sequence Alignment, Trans-Activators, Transcription Factors, beta Catenin
Mol. Cell
Date: Aug. 27, 2004
PubMed ID: 15327769
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