Mechanism for selectivity-inactivation coupling in KcsA potassium channels

Area of Science:

• Biophysics
• Molecular Biology
• Structural Biology

Background:

• Prokaryotic potassium (K+) channels, like KcsA, possess a selectivity filter with a GYG motif, crucial for ion selectivity.
• C-type inactivation leads to variable cation selectivity within K+ channels.
• Understanding the molecular basis of K+ channel selectivity and inactivation is vital for numerous physiological processes.

Purpose of the Study:

• To investigate the molecular mechanism linking C-type inactivation and altered cation selectivity in the KcsA channel.
• To elucidate the role of the E71-D80 interaction in K+ channel function and selectivity.

Main Methods:

• Utilized a noninactivating E71A mutant of the KcsA channel.
• Performed electrophysiological measurements, including flux assays and intracellular Na+ block analysis.
• Determined crystal structures of the E71A mutant under various ionic conditions.

Main Results:

• The E71A mutation disrupted a key hydrogen bond, leading to decreased K+ selectivity and increased Na+ permeation.
• Crystal structures revealed that E71A channels adopt a 'flipped' selectivity filter conformation, distinct from the inactivated 'collapsed' state.
• The E71-D80 interaction was identified as critical for both favoring inactivation and maintaining high K+ selectivity.

Conclusions:

• A molecular mechanism linking K+ channel inactivation and selectivity was proposed, highlighting the importance of the E71-D80 interaction.
• This mechanism, involving conformational changes in the selectivity filter, may be conserved in other channels with the GYG motif.
• The findings provide insights into the regulation of ion channel function and selectivity.