title: Interfacial gating triad is crucial for electromechanical transduction in voltage-activated potassium channels.
abstract: Voltage-dependent potassium channels play a crucial role in electrical excitability and cellular signaling by regulating potassium ion flux across membranes. Movement of charged residues in the voltage-sensing domain leads to a series of conformational changes that culminate in channel opening in response to changes in membrane potential. However, the molecular machinery that relays these conformational changes from voltage sensor to the pore is not well understood. Here we use generalized interaction-energy analysis (GIA) to estimate the strength of site-specific interactions between amino acid residues putatively involved in the electromechanical coupling of the voltage sensor and pore in the outwardly rectifying KV channel. We identified candidate interactors at the interface between the S4-S5 linker and the pore domain using a structure-guided graph theoretical approach that revealed clusters of conserved and closely packed residues. One such cluster, located at the intracellular intersubunit interface, comprises three residues (arginine 394, glutamate 395, and tyrosine 485) that interact with each other. The calculated interaction energies were 3-5 kcal, which is especially notable given that the net free-energy change during activation of the Shaker KV channel is ∼14 kcal. We find that this triad is delicately maintained by balance of interactions that are responsible for structural integrity of the intersubunit interface while maintaining sufficient flexibility at a critical gating hinge for optimal transmission of force to the pore gate.
authors.affiliation: Graduate Program in Biophysics and Department of Neuroscience, University of Wisconsin, Madison, WI 53705 Graduate Program in Biophysics and Department of Neuroscience, University of Wisconsin, Madison, WI 53705.
authors.forename: Sandipan
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Graduate Program in Biophysics and Department of Neuroscience, University of Wisconsin, Madison, WI 53705 Graduate Program in Biophysics and Department of Neuroscience, University of Wisconsin, Madison, WI 53705.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Haehnel
authors.affiliation: Graduate Program in Biophysics and Department of Neuroscience, University of Wisconsin, Madison, WI 53705 Graduate Program in Biophysics and Department of Neuroscience, University of Wisconsin, Madison, WI 53705 chanda@wisc.edu.
authors.forename: Baron
authors.initials: B
authors.lastname: Chanda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015640:Ion Channel Gating; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D051637:Shaker Superfamily of Potassium Channels / Q000737:chemistry*; D055672:Static Electricity; D014981:Xenopus
chemical_list: D051637:Shaker Superfamily of Potassium Channels