Abstract
Voltage-dependent K+ (Kv) channels gate open in response to the membrane voltage. To further our understanding of how cell membrane voltage regulates the opening of a Kv channel, we have studied the protein interfaces that attach the voltage-sensor domains to the pore. In the crystal structure, three physical interfaces exist. Only two of these consist of amino acids that are co-evolved across the interface between voltage sensor and pore according to statistical coupling analysis of 360 Kv channel sequences. A first co-evolved interface is formed by the S4-S5 linkers (one from each of four voltage sensors), which form a cuff surrounding the S6-lined pore opening at the intracellular surface. The crystal structure and published mutational studies support the hypothesis that the S4-S5 linkers convert voltage-sensor motions directly into gate opening and closing. A second co-evolved interface forms a small contact surface between S1 of the voltage sensor and the pore helix near the extracellular surface. We demonstrate through mutagenesis that this interface is necessary for the function and/or structure of two different Kv channels. This second interface is well positioned to act as a second anchor point between the voltage sensor and the pore, thus allowing efficient transmission of conformational changes to the pore's gate.
Highlights
Voltage-dependent ion channels mediate electrical impulses and enable the rapid transfer of information along the cell surface
In the atomic structures of Kv1.2 and a mutant known as paddle chimera, the S4-S5 linker helices are positioned in such a manner that conformational changes within the voltage sensors can be transmitted to the inner helices in order to facilitate constriction or dilation of the pore [4,7]
The voltage-sensor domains transmit voltage-driven conformational changes to the pore. To understand how this ‘‘electromechanical coupling’’ mechanism works, we have studied the protein–protein interfaces that connect the voltage sensors to the pore using bioinformatics, electrophysiological recordings, sitedirected mutagenesis, and chemical cross-linking
Summary
Voltage-dependent ion channels mediate electrical impulses and enable the rapid transfer of information along the cell surface. These impulses underlie information processing by the nervous system, muscle contraction, and many other important biological processes [1]. Members of the large family of voltage-dependent cation channels— including Kþ, Naþ, and Ca2þ selective channels—all share a common architecture consisting of a central ion-conduction pore surrounded by four voltage sensors located on the perimeter. In the atomic structures of Kv1.2 and a mutant known as paddle chimera, the S4-S5 linker helices are positioned in such a manner that conformational changes within the voltage sensors can be transmitted to the inner helices in order to facilitate constriction or dilation of the pore [4,7]
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