PI(3,4,5)P 3 and PI(4,5)P 2 Lipids Target Proteins with Polybasic Clusters to the Plasma Membrane

• DOI: 10.1126/science.1134389
• Publication Date: 2006-11-10T01:58:44Z
• Authors: Won Do Heo; Takanari Inoue; Wei Sun Park; Man Lyang Kim; Byung Ouk Park; Thomas J. Wandless; Tobias Meyer
• Keywords: Phosphatidylinositol 4,5-Diphosphate; 0303 health sciences; ADP-Ribosylation Factors; Amino Acid Motifs; Cell Membrane; Molecular Sequence Data; Static Electricity; Second Messenger Systems; GTP Phosphohydrolases; Kinetics; Mice; 03 medical and health sciences; Phosphatidylinositol Phosphates; rab GTP-Binding Proteins; NIH 3T3 Cells; ras Proteins; Animals; Humans; Amino Acid Sequence; Hydrophobic and Hydrophilic Interactions; HeLa Cells; Signal Transduction

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)P 2 ] lipids, we developed a chemical phosphatase activation method to deplete PM PI(4,5)P 2 . Unexpectedly, proteins with polybasic clusters dissociated from the PM only when both PI(4,5)P 2 and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] were depleted, arguing that both lipid second messengers jointly regulate PM targeting.