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PI(3,4,5)P3 and PI(4,5)P2 Lipids Target Proteins with Polybasic Clusters to the Plasma Membrane
Won Do Heo,1Takanari Inoue,1Wei Sun Park,1Man Lyang Kim,1Byung Ouk Park,2Thomas J. Wandless,1Tobias Meyer1*
Many signaling, cytoskeletal, and transport proteins have tobe localized to the plasma membrane (PM) in order to carry outtheir function. We surveyed PM-targeting mechanisms by imagingthe subcellular localization of 125 fluorescent proteinconjugatedRas, Rab, Arf, and Rho proteins. Out of 48 proteins that werePM-localized, 37 contained clusters of positively charged aminoacids. To test whether these polybasic clusters bind negativelycharged phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] lipids,we developed a chemical phosphatase activation method to depletePM PI(4,5)P2. Unexpectedly, proteins with polybasic clustersdissociated from the PM only when both PI(4,5)P2 and phosphatidylinositol3,4,5-trisphosphate [PI(3,4,5)P3] were depleted, arguing thatboth lipid second messengers jointly regulate PM targeting.
1 Department of Molecular Pharmacology, 318 Campus Drive, Clark Building, Stanford University Medical School, Stanford, CA 94305, USA. 2 Division of Applied Life Science (BK21 Program) and Environmental Biotechnology National Core Research Center, Gyeongsang National University, Jinju 660-701, Korea.
* To whom correspondence should be addressed. E-mail: tobias1{at}stanford.edu
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