TY - JOUR
T1 - Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a Ligand-gated ion channel
AU - Tong, Ailing
AU - Hsu, Fong Fu
AU - Schmidpeter, Philipp Am
AU - Nimigean, Crina M.
AU - Sharp, Liam
AU - Brannigan, Grace
AU - Cheng, Wayland Wl
N1 - Funding Information:
The National Institute of General Medical Sciences (K08GM126336) and Center for the Investigation of Membrane Excitability Diseases provided the majority of support for this study including funding for study design, data collection and analysis, and the decision to submit the manuscript for publication. The American Heart Association (18POST33960309) and National Institute of General Medical Sciences (R01GM124451) supported the stopped-flow fluorescence recordings.
Publisher Copyright:
© 2019, eLife Sciences Publications Ltd. All rights reserved.
PY - 2019/11
Y1 - 2019/11
N2 - Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization In contrast, a mutation that decreases ELIC desensitization, increases POPG binding The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.
AB - Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization In contrast, a mutation that decreases ELIC desensitization, increases POPG binding The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.
UR - http://www.scopus.com/inward/record.url?scp=85075034989&partnerID=8YFLogxK
U2 - 10.7554/eLife.50766
DO - 10.7554/eLife.50766
M3 - Article
C2 - 31724949
AN - SCOPUS:85075034989
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e50766
ER -