Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled.
Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled.
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PIP5K1A 结构解析揭示了其二聚化和散乱调节的分子机制
DOI：
10.1038/ncomms9205
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发表时间：
2015-09-14
影响因子：
16.6
通讯作者：
Wu D
中科院分区：
文献类型：
--
作者：
Hu J;Yuan Q;Kang X;Qin Y;Li L;Ha Y;Wu D
I型磷脂酰肌醇磷酸激酶（PIP 5 K1）磷酸化磷脂酰肌醇4-磷酸（PtdIns 4P）的头部基团以产生PtdIns 4，5 P2，其在包括Wnt信号传导在内的广泛的细胞功能中起重要作用。然而，由于缺乏其结构信息，阻碍了对其调控的理解。在这里，我们报告的晶体结构的催化结构域的斑马鱼PIP 5 K1 A在3.3纳米分辨率。该分子形成侧对侧二聚体。PIP 5 K1 A的突变研究揭示了两个相邻的界面，用于二聚化以及与Wnt信号分子DIX结构域的相互作用。尽管这些界面位于催化/底物结合位点的远端，但通过二聚化或与DIX的相互作用与这些界面结合刺激PIP 5 K1催化活性。DIX结合另外增强PIP 5 K1底物结合。因此，这项研究阐明了这种脂质激酶的调节机制，并提供了一个范例，了解PIP 5 K1的相互作用分子的调节。
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.