Metabolically stabilized derivatives of phosphatidylinositol 4-phosphate: synthesis and applications.
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).
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Ju
J
He
Joanna
J
Gajewiak
Jordan L
JL
Scott
Denghuang
D
Gong
Muzaffar
M
Ali
Michael D
MD
Best
Glenn D
GD
Prestwich
Robert V
RV
Stahelin
Tatiana G
TG
Kutateladze
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008051:Lipid Bilayers; D009682:Magnetic Resonance Spectroscopy; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000378:metabolism; D015394:Molecular Structure; D010713:Phosphatidylcholines / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry* / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D007295:Inositol Phosphates; D008024:Ligands; D008051:Lipid Bilayers; D015335:Molecular Probes; C487037:PLEKHA3 protein, human; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D011993:Recombinant Fusion Proteins; C037178:phosphatidylinositol 4-phosphate; C057561:1-palmitoyl-2-oleoylphosphatidylethanolamine; C044259:inositol 1,4-bis(phosphate); C028694:1-palmitoyl-2-oleoylphosphatidylcholine