ZFIN ID: ZDB-PUB-150916-15
Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled
Hu, J., Yuan, Q., Kang, X., Qin, Y., Li, L., Ha, Y., Wu, D.
Date: 2015
Source: Nature communications   6: 8205 (Journal)
Registered Authors: Li, Lin
Keywords: Kinases, Structural biology
MeSH Terms:
  • Adaptor Proteins, Signal Transducing/metabolism*
  • Animals
  • Binding Sites
  • Calorimetry
  • Catalytic Domain
  • Circular Dichroism
  • Crystallization
  • Crystallography, X-Ray
  • Dimerization*
  • Dishevelled Proteins
  • HEK293 Cells
  • Humans
  • Phosphatidylinositol 4,5-Diphosphate/metabolism
  • Phosphatidylinositol Phosphates/metabolism
  • Phosphoproteins/metabolism*
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)/chemistry
  • Phosphotransferases (Alcohol Group Acceptor)/metabolism*
  • Protein Structure, Tertiary
  • Zebrafish
PubMed: 26365782 Full text @ Nat. Commun.
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.