title: PI(3,4,5)P3 and PI(4,5)P2 lipids target proteins with polybasic clusters to the plasma membrane.
abstract: Many signaling, cytoskeletal, and transport proteins have to be localized to the plasma membrane (PM) in order to carry out their function. We surveyed PM-targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Out of 48 proteins that were PM-localized, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] lipids, we developed a chemical phosphatase activation method to deplete PM PI(4,5)P2. Unexpectedly, proteins with polybasic clusters dissociated from the PM only when both PI(4,5)P2 and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] were depleted, arguing that both lipid second messengers jointly regulate PM targeting.
authors.affiliation: Department of Molecular Pharmacology, 318 Campus Drive, Clark Building, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Won Do
authors.initials: WD
authors.lastname: Heo
authors.forename: Takanari
authors.initials: T
authors.lastname: Inoue
authors.forename: Wei Sun
authors.initials: WS
authors.lastname: Park
authors.forename: Man Lyang
authors.initials: ML
authors.lastname: Kim
authors.forename: Byung Ouk
authors.initials: BO
authors.lastname: Park
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wandless
authors.forename: Tobias
authors.initials: T
authors.lastname: Meyer
mesh_terms: D020727:ADP-Ribosylation Factors / Q000737:chemistry / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction; D055672:Static Electricity; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D020558:GTP Phosphohydrolases; D020727:ADP-Ribosylation Factors; D020691:rab GTP-Binding Proteins; D018631:ras Proteins; D020741:rho GTP-Binding Proteins