title: Migration of PIP2 lipids on voltage-gated potassium channel surface influences channel deactivation.
abstract: Published studies of lipid-protein interactions have mainly focused on lipid binding to an individual site of the protein. Here, we show that a lipid can migrate between different binding sites in a protein and this migration modulates protein function. Voltage-gated potassium (Kv) channels have several potential binding sites for phosphatidylinositol-4,5-bisphosphate (PIP2). Our molecular dynamics (MD) simulations on the KCNQ2 channel reveal that PIP2 preferentially binds to the S4-S5 linker when the channel is in the open state while maintains a certain probability of migrating to the S2-S3 linker. Guided by the MD results, electrophysiological experiments using KCNQ2, KCNQ1, and hERG channels show that the migration of PIP2 toward the S2-S3 linker controls the deactivation rate of the channel. The data suggest that PIP2 can migrate between different binding sites in Kv channels with significant impacts on channel deactivation, casting new insights into the dynamics and physiological functions of lipid-protein interactions.
authors.affiliation: State Key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Qiansen
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Yunguang
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Zanyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Zhuxi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry* / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D051658:KCNQ2 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D024642:Potassium Channels, Voltage-Gated