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

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  • Jian Hu

    (Yale School of Medicine
    Present address: Department of Biochemistry and Molecular Biology and Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, USA)

  • Qianying Yuan

    (Yale School of Medicine
    Vascular Biology and Therapeutic Program, Yale School of Medicine)

  • Xue Kang

    (Yale School of Medicine
    Vascular Biology and Therapeutic Program, 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
    Vascular Biology and Therapeutic Program, Yale School of Medicine)

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.

Suggested Citation

  • Jian Hu & Qianying Yuan & Xue Kang & Yuanbo Qin & Lin Li & Ya Ha & Dianqing Wu, 2015. "Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9205
    DOI: 10.1038/ncomms9205
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