Voltage Sensor Conformations Induced by LQTS-associated Mutations in hERG Potassium Channels

Area of Science:

• Molecular Biology
• Biophysics
• Cardiology

Background:

• Voltage sensors in hERG K+ channels are crucial for cardiac electrical activity.
• Mutations in these sensors are linked to Long QT syndrome, affecting cardiac rhythm.
• The precise mechanisms by which these mutations alter channel gating remain poorly understood.

Purpose of the Study:

• To investigate the structural and conformational changes in hERG voltage sensors caused by mutations associated with Long QT syndrome.
• To elucidate the molecular mechanisms underlying altered channel gating in these mutants.

Main Methods:

• Utilized fluorescence lifetime imaging microscopy (FLIM) and transition metal FRET (tmFRET).
• Employed dual stop-codon mediated noncanonical amino acid incorporation.
• Performed molecular dynamics (MD) simulations.

Main Results:

• Identified distinct intermediate voltage-sensor conformations in mutant hERG channels.
• Phasor plot analysis revealed multiple FRET states in mutants, unlike the single high-FRET state in controls.
• Intermediate FRET states correlated with specific mutation sites and MD-simulated conformations.

Conclusions:

• Provides novel insights into the structural basis of cardiac channelopathies.
• Highlights specific intermediate voltage-sensor conformations underlying cardiac arrhythmias.
• Enhances understanding of electromechanical coupling in hERG channels.