Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin

EMBO J. 2012 Mar 7;31(5):1308-19. doi: 10.1038/emboj.2011.496. Epub 2012 Jan 17.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cadherins / metabolism*
  • 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 / chemistry*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Cadherins
  • CBLL1 protein, human
  • Ubiquitin-Protein Ligases

Associated data

  • PDB/3VK6