biostudies-literatureStover LWelch FoundationNational Institute of General Medical SciencesNIGMS NIH HHS1516-1522https://www.ebi.ac.uk/biostudies/studies/S-EPMC11228984biostudies-literatureUnknown35(7)TREK2, a two-pore domain potassium channel, is recognized for its regulation by various stimuli, including lipids. While previous members of the TREK subfamily, TREK1 and TRAAK, have been investigated to elucidate their lipid affinity and selectivity, TREK2 has not been similarly studied in this regard. Our findings indicate that while TRAAK and TREK2 exhibit similarities in terms of electrostatics and share an overall structural resemblance, there are notable distinctions in their interaction with lipids. Specifically, SAPI(4,5)P2,1-stearoyl-2-arachidonoyl-<i>sn</i>-glycero-3-phospho-(1'-myo-inositol-4',5'-bisphosphate) exhibits a strong affinity for TREK2, surpassing that of dOPI(4,5)P2,1,2-dioleoyl-<i>sn</i>-glycero-3-phospho-(1'-myo-inositol-4',5'-bisphosphate), which differs in its acyl chains. TREK2 displays lipid binding preferences not only for the headgroup of lipids but also toward the acyl chains. Functional studies draw a correlation for lipid binding affinity and activity of the channel. These findings provide important insight into elucidating the molecular prerequisites for specific lipid binding to TREK2 important for function.Journal of the American Society for Mass SpectrometryTREK2 Lipid Binding Preferences Revealed by Native Mass Spectrometry.PMC11228984R01GM139876R01GM138863RM1GM145416RM1 GM145416A-2106-20220331R01 GM138863R01 GM139876RM1GM149374RM1 GM149374Schrecke SZhu YLaganowsky AStover LfalseTREK2 Lipid Binding Preferences Revealed by Native Mass Spectrometry.TREK2, a two-pore domain potassium channel, is recognized for its regulation by various stimuli, including lipids. While previous members of the TREK subfamily, TREK1 and TRAAK, have been investigated to elucidate their lipid affinity and selectivity, TREK2 has not been similarly studied in this regard. Our findings indicate that while TRAAK and TREK2 exhibit similarities in terms of electrostatics and share an overall structural resemblance, there are notable distinctions in their interaction with lipids. Specifically, SAPI(4,5)P2,1-stearoyl-2-arachidonoyl-<i>sn</i>-glycero-3-phospho-(1'-myo-inositol-4',5'-bisphosphate) exhibits a strong affinity for TREK2, surpassing that of dOPI(4,5)P2,1,2-dioleoyl-<i>sn</i>-glycero-3-phospho-(1'-myo-inositol-4',5'-bisphosphate), which differs in its acyl chains. TREK2 displays lipid binding preferences not only for the headgroup of lipids but also toward the acyl chains. Functional studies draw a correlation for lipid binding affinity and activity of the channel. These findings provide important insight into elucidating the molecular prerequisites for specific lipid binding to TREK2 important for function.2024-01-01T00:00:00Z2024 Jul2024-11-20T23:51:29.324Z2024-11-20T23:51:29.324ZS-EPMC112289843884343810.1021/jasms.4c00112