Migration of PIP2 lipids between the S4-S5 linker and the S2-S3 linker on the surface of voltage-gated potassium channels controls the deactivation rate of the channels.
The migration of PIP2 lipids between binding sites on voltage-gated potassium channels dynamically regulates channel deactivation, providing new mechanistic insights into lipid-protein interactions.
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.
Chen et al. (Thu,) conducted a other in Voltage-gated potassium channel gating. Mutations altering PIP2 binding sites (e.g., K230N, W497K) vs. Wild-type channels was evaluated on Deactivation time constant. Migration of PIP2 lipids between the S4-S5 linker and the S2-S3 linker on the surface of voltage-gated potassium channels controls the deactivation rate of the channels.
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