Two separate interfaces between the voltage sensor and pore are required for the function of voltage-dependent K(+)...

Area of Science:

• Molecular Biology
• Biophysics
• Structural Biology

Background:

• Voltage-dependent potassium (Kv) channels are crucial for regulating cellular electrical activity.
• Understanding the precise mechanisms of Kv channel gating by membrane voltage remains an active area of research.

Purpose of the Study:

• To elucidate the structural and functional roles of protein interfaces connecting Kv channel voltage-sensor domains to the pore.
• To identify co-evolved amino acid residues at these interfaces that are critical for channel gating.

Main Methods:

• Analysis of crystal structures of Kv channels.
• Statistical coupling analysis of 360 Kv channel sequences to identify co-evolved residues.
• Site-directed mutagenesis studies to assess the functional impact of interface mutations.

Main Results:

• Three physical interfaces between voltage sensors and the pore were identified.
• Two of these interfaces exhibit co-evolved amino acids, suggesting functional importance.
• The S4-S5 linker interface acts as an intracellular cuff, directly converting voltage-sensor movements to gate operation.
• A second extracellular interface between S1 and the pore helix is essential for Kv channel function and/or structure.

Conclusions:

• The S4-S5 linker interface is a primary mechanism for translating voltage changes into Kv channel gating.
• A second, extracellular interface serves as an additional anchor, ensuring efficient conformational change transmission to the gate.
• These co-evolved interfaces are critical for the structural integrity and voltage-dependent function of Kv channels.