TREK2 Lipid Binding Preferences Revealed by Native Mass Spectrometry

Area of Science:

• Biophysics
• Molecular Biology
• Neuroscience

Background:

• TREK2 is a two-pore domain potassium channel.
• Lipids are known regulators of TREK channel activity.
• Previous studies focused on TREK1 and TRAAK lipid interactions, but TREK2 remains understudied.

Purpose of the Study:

• To investigate the lipid binding affinity and selectivity of TREK2.
• To understand the molecular basis of TREK2-lipid interactions.
• To correlate lipid binding with TREK2 channel function.

Main Methods:

• Computational modeling to assess electrostatics and structural resemblance.
• Lipid binding assays using specific phosphoinositides.
• Functional electrophysiology to measure channel activity.

Main Results:

• TREK2 shares structural and electrostatic similarities with TRAAK but exhibits distinct lipid interactions.
• TREK2 shows a strong preference for 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-(1'-myo-inositol-4',5'-bisphosphate) (SAPI(4,5)P2) over 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol-4',5'-bisphosphate) (dOPI(4,5)P2).
• TREK2's lipid binding preference extends to both lipid headgroups and acyl chains, correlating with channel activity.

Conclusions:

• TREK2 exhibits specific lipid binding preferences, influenced by both headgroup and acyl chain composition.
• These findings elucidate the molecular determinants of TREK2's interaction with lipids.
• Understanding these interactions is crucial for deciphering TREK2 function in cellular processes.