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

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

Author information

1
Department of Biological Sciences, National University of Singapore, Singapore.

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.

PMID:
22252131
PMCID:
PMC3298002
DOI:
10.1038/emboj.2011.496
[Indexed for MEDLINE]
Free PMC Article

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