| Structural highlights
Function
[HAKAI_MOUSE] Promotes ubiquitination of several tyrosine-phosphorylated Src substrates, including CDH1, CTTN and DOK1. Targets CDH1 for endocytosis and degradation.[1] [2]
Publication Abstract from PubMed
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.
Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin.,Mukherjee M, Chow SY, Yusoff P, Seetharaman J, Ng C, Sinniah S, Koh XW, Asgar NF, Li D, Yim D, Jackson RA, Yew J, Qian J, Iyu A, Lim YP, Zhou X, Sze SK, Guy GR, Sivaraman J EMBO J. 2012 Jan 17;31(5):1308-19. doi: 10.1038/emboj.2011.496. PMID:22252131[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HE, Behrens J, Sommer T, Birchmeier W. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol. 2002 Mar;4(3):222-31. PMID:11836526 doi:10.1038/ncb758
- ↑ Mukherjee M, Chow SY, Yusoff P, Seetharaman J, Ng C, Sinniah S, Koh XW, Asgar NF, Li D, Yim D, Jackson RA, Yew J, Qian J, Iyu A, Lim YP, Zhou X, Sze SK, Guy GR, Sivaraman J. Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin. EMBO J. 2012 Jan 17;31(5):1308-19. doi: 10.1038/emboj.2011.496. PMID:22252131 doi:10.1038/emboj.2011.496
- ↑ Mukherjee M, Chow SY, Yusoff P, Seetharaman J, Ng C, Sinniah S, Koh XW, Asgar NF, Li D, Yim D, Jackson RA, Yew J, Qian J, Iyu A, Lim YP, Zhou X, Sze SK, Guy GR, Sivaraman J. Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin. EMBO J. 2012 Jan 17;31(5):1308-19. doi: 10.1038/emboj.2011.496. PMID:22252131 doi:10.1038/emboj.2011.496
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