title: Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin.
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.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore.
authors.forename: Manjeet
authors.initials: M
authors.lastname: Mukherjee
authors.forename: Soah Yee
authors.initials: SY
authors.lastname: Chow
authors.forename: Permeen
authors.initials: P
authors.lastname: Yusoff
authors.forename: J
authors.initials: J
authors.lastname: Seetharaman
authors.forename: Cherlyn
authors.initials: C
authors.lastname: Ng
authors.forename: Saravanan
authors.initials: S
authors.lastname: Sinniah
authors.forename: Xiao Woon
authors.initials: XW
authors.lastname: Koh
authors.forename: Nur Farehan M
authors.initials: NF
authors.lastname: Asgar
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Yim
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Jackson
authors.forename: Jingxi
authors.initials: J
authors.lastname: Yew
authors.forename: Jingru
authors.initials: J
authors.lastname: Qian
authors.forename: Audrey
authors.initials: A
authors.lastname: Iyu
authors.forename: Yoon Pin
authors.initials: YP
authors.lastname: Lim
authors.forename: Xingding
authors.initials: X
authors.lastname: Zhou
authors.forename: Siu Kwan
authors.initials: SK
authors.lastname: Sze
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Guy
authors.forename: J
authors.initials: J
authors.lastname: Sivaraman
mesh_terms: D000595:Amino Acid Sequence; D015820:Cadherins / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D015820:Cadherins; C471638:CBLL1 protein, human; D044767:Ubiquitin-Protein Ligases