Metabolically stabilized derivatives of phosphatidylinositol 4-phosphate: synthesis and applications

Chem Biol. 2011 Oct 28;18(10):1312-9. doi: 10.1016/j.chembiol.2011.07.022.

Abstract

Phosphatidylinositol 4-phosphate (PtdIns(4)P) lipid is an essential component of eukaryotic membranes and a marker of the Golgi complex. Here, we developed metabolically stabilized (ms) analogs of PtdIns(4)P and the inositol 1,4-bisphosphate (IP(2)) head group derivative and demonstrated that these compounds can substitute the natural lipid fully retaining its physiological activities. The methylenephosphonate (MP) and phosphorothioate (PT) analogs of PtdIns(4)P and the aminohexyl (AH)-IP(2) probe are recognized by the PtdIns(4)P-specific PH domain of four phosphate adaptor protein 1 (FAPP1). Binding of FAPP1 to the PtdIns(4)P derivatives stimulates insertion of the PH domain into the lipid layers and induces tubulation of membranes. Both ms analogs and IP(2) probes could be invaluable for identifying protein effectors and characterizing PtdIns(4)P-dependent signaling cascades within the trans-Golgi network (TGN).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Binding Sites
  • Inositol Phosphates / chemistry
  • Inositol Phosphates / metabolism
  • Ligands
  • Lipid Bilayers
  • Magnetic Resonance Spectroscopy
  • Molecular Probes / chemical synthesis*
  • Molecular Probes / metabolism
  • Molecular Structure
  • Phosphatidylcholines / chemistry
  • Phosphatidylethanolamines / chemistry
  • Phosphatidylinositol Phosphates / chemistry*
  • Phosphatidylinositol Phosphates / metabolism*
  • Phosphatidylinositols / metabolism
  • Protein Conformation
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • Inositol Phosphates
  • Ligands
  • Lipid Bilayers
  • Molecular Probes
  • PLEKHA3 protein, human
  • Phosphatidylcholines
  • Phosphatidylethanolamines
  • Phosphatidylinositol Phosphates
  • Phosphatidylinositols
  • Recombinant Fusion Proteins
  • phosphatidylinositol 4-phosphate
  • 1-palmitoyl-2-oleoylphosphatidylethanolamine
  • inositol 1,4-bis(phosphate)
  • 1-palmitoyl-2-oleoylphosphatidylcholine