Abstract
Among critical aspects of voltage-gated potassium (Kv) channels' functioning is the effective communication between their two composing domains, the voltage sensor (VSD) and the pore. This communication, called coupling, might be transmitted directly through interactions between these domains and, as recently proposed, indirectly through interactions with phosphatidylinositol-4,5-bisphosphate (PIP2), a minor lipid of the inner plasma membrane leaflet. Here, we show how the two components of coupling, mediated by protein-protein or protein-lipid interactions, both contribute in the Kv7.1 functioning. On the one hand, using molecular dynamics simulations, we identified a Kv7.1 PIP2 binding site that involves residues playing a key role in PIP2-dependent coupling. On the other hand, combined theoretical and experimental approaches have shown that the direct interaction between the segments of the VSD (S4–S5) and the pore (S6) is weakened by electrostatic repulsion. Finally, we conclude that due to weakened protein-protein interactions, the PIP2-dependent coupling is especially prominent in Kv7.1.
Highlights
Among critical aspects of voltage-gated potassium (Kv) channels’ functioning is the effective communication between their two composing domains, the voltage sensor (VSD) and the pore
PIP2 interacts with the voltage sensor domain (VSD) and the pore domain (PD) of Kv7.1 in a state dependent manner
Coupling is an effective communication between the VSD and the PD of a channel that provides triggering conformational changes in the pore as a response of those in the voltage sensor
Summary
Among critical aspects of voltage-gated potassium (Kv) channels’ functioning is the effective communication between their two composing domains, the voltage sensor (VSD) and the pore. This communication, called coupling, might be transmitted directly through interactions between these domains and, as recently proposed, indirectly through interactions with phosphatidylinositol-4,5-bisphosphate (PIP2), a minor lipid of the inner plasma membrane leaflet. In Kv7.1 channels, in addition to protein-protein interactions, another component of coupling, protein-lipid, was recently proposed[9] This involves phosphatidylinositol-4,5-bisphosphate (PIP2), a minor lipid of the inner membrane leaflet[10]. What is the gain-offunction mutagenesis effect that leads to observed increase of ionic current? We attempt here to answer these outstanding questions using combined theoretical and experimental approaches
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