Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled

Jian Hu, Qianying Yuan, Xue Kang, Yuanbo Qin, Lin Li, Ya Ha () and Dianqing Wu ()
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Jian Hu: Yale School of Medicine
Qianying Yuan: Yale School of Medicine
Xue Kang: Yale School of Medicine
Yuanbo Qin: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Lin Li: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Ya Ha: Yale School of Medicine
Dianqing Wu: Yale School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9205

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