title: PIP₂-dependent coupling is prominent in Kv7.1 due to weakened interactions between S4-S5 and S6.
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.
authors.affiliation: 1] Université de Lorraine, Theory, Modeling and Simulations, UMR 7565, Vandoeuvre-lés-Nancy, F-54506 France [2] Lomonosov Moscow State University, Moscow, 119991, Russian Federation.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Kasimova
authors.affiliation: Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Cardiac Bioelectricity and Arrhythmia Center, Washington University in St. Louis, St. Louis, MO 63130-4862.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zaydman
authors.affiliation: Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Cardiac Bioelectricity and Arrhythmia Center, Washington University in St. Louis, St. Louis, MO 63130-4862.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Cui
authors.affiliation: 1] Université de Lorraine, Theory, Modeling and Simulations, UMR 7565, Vandoeuvre-lés-Nancy, F-54506 France [2] Centre National de la Recherche Scientifique, UMR 7565, Vandoeuvre-lés-Nancy, F-54506 France.
authors.forename: Mounir
authors.initials: M
authors.lastname: Tarek
mesh_terms: D001665:Binding Sites; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D055672:Static Electricity
chemical_list: D051657:KCNQ1 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate