2. Academic Validation
  3. Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin

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.
Manjeet Mukherjee 1,  Soah Yee Chow,  Permeen Yusoff,  J Seetharaman,  Cherlyn Ng,  Saravanan Sinniah,  Xiao Woon Koh,  Nur Farehan M Asgar,  Dan Li,  Daniel Yim,  Rebecca A Jackson,  Jingxi Yew,  Jingru Qian,  Audrey Iyu,  Yoon Pin Lim,  Xingding Zhou,  Siu Kwan Sze,  Graeme R Guy,  J Sivaraman
Affiliations

Affiliation

  • 1 Department of Biological Sciences, National University of Singapore, Singapore.
PMID: 22252131 DOI: 10.1038/emboj.2011.496
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.

Figures