title: Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled.
abstract: Type I phosphatidylinositol phosphate kinase (PIP5K1) phosphorylates the head group of phosphatidylinositol 4-phosphate (PtdIns4P) to generate PtdIns4,5P2, which plays important roles in a wide range of cellular functions including Wnt signalling. However, the lack of its structural information has hindered the understanding of its regulation. Here we report the crystal structure of the catalytic domain of zebrafish PIP5K1A at 3.3 Å resolution. This molecule forms a side-to-side dimer. Mutagenesis study of PIP5K1A reveals two adjacent interfaces for the dimerization and interaction with the DIX domain of the Wnt signalling molecule dishevelled. Although these interfaces are located distally to the catalytic/substrate-binding site, binding to these interfaces either through dimerization or the interaction with DIX stimulates PIP5K1 catalytic activity. DIX binding additionally enhances PIP5K1 substrate binding. Thus, this study elucidates regulatory mechanisms for this lipid kinase and provides a paradigm for the understanding of PIP5K1 regulation by their interacting molecules.
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, Connecticut 06520 USA.
authors.forename: Qianying
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, Connecticut 06520 USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Kang
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yuanbo
authors.initials: Y
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Ya
authors.initials: Y
authors.lastname: Ha
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, Connecticut 06520 USA.
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002151:Calorimetry; D020134:Catalytic Domain; D002942:Circular Dichroism; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D000072261:Dishevelled Proteins; D057809:HEK293 Cells; D006801:Humans; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015027:Zebrafish
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; C037178:phosphatidylinositol 4-phosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase