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Nat Commun. 2015 Sep 14;6:8205. doi: 10.1038/ncomms9205.

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

Hu J1, Yuan Q1,2, Kang X1,2, Qin Y3, Li L3, Ha Y1, Wu D1,2.

Author information

1
Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
2
Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, Connecticut 06520 USA.
3
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

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.

PMID:
26365782
PMCID:
PMC4570271
DOI:
10.1038/ncomms9205
[Indexed for MEDLINE]
Free PMC Article

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