Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin.
Phosphotyrosine-binding domains, typified by the SH2 (Src homology 2) and PTB domains, are critical upstream components of signal transduction pathways. The E3 ubiquitin ligase Hakai targets tyrosine-phosphorylated E-cadherin via an uncharacterized domain. In this study, the crystal structure of Hakai (amino acids 106-206) revealed that it forms an atypical, zinc-coordinated ... homodimer by utilizing residues from the phosphotyrosine-binding domain of two Hakai monomers. Hakai dimerization allows the formation of a phosphotyrosine-binding pocket that recognizes specific phosphorylated tyrosines and flanking acidic amino acids of Src substrates, such as E-cadherin, cortactin and DOK1. NMR and mutational analysis identified the Hakai residues required for target binding within the binding pocket, now named the HYB domain. ZNF645 also possesses a HYB domain but demonstrates different target specificities. The HYB domain is structurally different from other phosphotyrosine-binding domains and is a potential drug target due to its novel structural features.
Mesh Terms:
Amino Acid Sequence, Cadherins, Crystallography, X-Ray, DNA Mutational Analysis, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Multimerization, Protein Structure, Quaternary, Protein Structure, Tertiary, Ubiquitin-Protein Ligases
Amino Acid Sequence, Cadherins, Crystallography, X-Ray, DNA Mutational Analysis, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Multimerization, Protein Structure, Quaternary, Protein Structure, Tertiary, Ubiquitin-Protein Ligases
EMBO J.
Date: Mar. 07, 2012
PubMed ID: 22252131
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