A gating charge transfer center in voltage sensors

Area of Science:

• Biophysics
• Molecular Biology
• Structural Biology

Background:

• Voltage sensors are crucial for the function of voltage-dependent ion channels and enzymes.
• Their rapid response to membrane voltage relies on the movement of charged amino acids (arginine or lysine) across the electric field.

Purpose of the Study:

• To identify the charge transfer center within voltage sensors responsible for amino acid movement.
• To investigate how specific mutations affect the preference for lysine over arginine.
• To understand how manipulating lysine placement can stabilize distinct voltage sensor conformations.

Main Methods:

• Utilized site-directed mutagenesis with natural and unnatural amino acids.
• Performed electrophysiological recordings to assess channel function.
• Employed X-ray crystallography to determine high-resolution structures.

Main Results:

• Identified a charge transfer center comprising a rigid cyclic cap and two negative charges that interact with positive charges.
• Demonstrated that specific mutations can alter the charge transfer center's preference for lysine over arginine.
• Showed that strategic placement of lysine residues can stabilize specific voltage sensor conformations.

Conclusions:

• The identified charge transfer center is key to voltage-dependent conformational changes.
• Lysine substitution offers a method to precisely control voltage sensor states.
• This provides a powerful approach to dissect voltage sensor mechanisms and their link to ion channel gating.