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Anionic Phospholipids Shift the Conformational Equilibrium of the Selectivity Filter in the KcsA Channel to the Conductive Conformation: Predicted Consequences on Inactivation

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Here, we report an allosteric effect of an anionic phospholipid on a model K+ channel, KcsA. The anionic lipid in mixed detergent–lipid micelles specifically induces a change in the conformational… Click to show full abstract

Here, we report an allosteric effect of an anionic phospholipid on a model K+ channel, KcsA. The anionic lipid in mixed detergent–lipid micelles specifically induces a change in the conformational equilibrium of the channel selectivity filter (SF) only when the channel inner gate is in the open state. Such change consists of increasing the affinity of the channel for K+, stabilizing a conductive-like form by maintaining a high ion occupancy in the SF. The process is highly specific in several aspects: First, lipid modifies the binding of K+, but not that of Na+, which remains unperturbed, ruling out a merely electrostatic phenomenon of cation attraction. Second, no lipid effects are observed when a zwitterionic lipid, instead of an anionic one, is present in the micelles. Lastly, the effects of the anionic lipid are only observed at pH 4.0, when the inner gate of KcsA is open. Moreover, the effect of the anionic lipid on K+ binding to the open channel closely emulates the K+ binding behaviour of the non-inactivating E71A and R64A mutant proteins. This suggests that the observed increase in K+ affinity caused by the bound anionic lipid should result in protecting the channel against inactivation.

Keywords: kcsa; conformational equilibrium; anionic lipid; selectivity filter; channel

Journal Title: Biomedicines
Year Published: 2023

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