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Article ; Online: State-dependent binding of cholesterol and an anionic lipid to the muscle-type Torpedo nicotinic acetylcholine receptor.

Ananchenko, Anna / Gao, Rui Yan / Dehez, François / Baenziger, John E

Communications biology

2024 Volume 7, Issue 1, Page(s) 437

Abstract: The ability of the Torpedo nicotinic acetylcholine receptor (nAChR) to undergo agonist-induced conformational transitions requires the presence of cholesterol and/or anionic lipids. Here we use recently solved structures along with multiscale molecular ... ...

Abstract	The ability of the Torpedo nicotinic acetylcholine receptor (nAChR) to undergo agonist-induced conformational transitions requires the presence of cholesterol and/or anionic lipids. Here we use recently solved structures along with multiscale molecular dynamics simulations to examine lipid binding to the nAChR in bilayers that have defined effects on nAChR function. We examine how phosphatidic acid and cholesterol, lipids that support conformational transitions, individually compete for binding with phosphatidylcholine, a lipid that does not. We also examine how the two lipids work synergistically to stabilize an agonist-responsive nAChR. We identify rapidly exchanging lipid binding sites, including both phospholipid sites with a high affinity for phosphatidic acid and promiscuous cholesterol binding sites in the grooves between adjacent transmembrane α-helices. A high affinity cholesterol site is confirmed in the inner leaflet framed by a key tryptophan residue on the MX α-helix. Our data provide insight into the dynamic nature of lipid-nAChR interactions and set the stage for a detailed understanding of the mechanisms by which lipids facilitate nAChR function at the neuromuscular junction.
MeSH term(s)	Animals ; Receptors, Nicotinic/metabolism ; Torpedo/metabolism ; Phospholipids ; Muscles/metabolism ; Phosphatidylcholines ; Cholesterol/metabolism
Chemical Substances	Receptors, Nicotinic ; Phospholipids ; Phosphatidylcholines ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2024-04-10
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-06106-8
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Article ; Online: A release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor.

Thompson, Mackenzie J / Mansoub Bekarkhanechi, Farid / Ananchenko, Anna / Nury, Hugues / Baenziger, John E

Nature communications

2024 Volume 15, Issue 1, Page(s) 1803

Abstract: Synaptic receptors respond to neurotransmitters by opening an ion channel across the post-synaptic membrane to elicit a cellular response. Here we use recent Torpedo acetylcholine receptor structures and functional measurements to delineate a key feature ...

Abstract	Synaptic receptors respond to neurotransmitters by opening an ion channel across the post-synaptic membrane to elicit a cellular response. Here we use recent Torpedo acetylcholine receptor structures and functional measurements to delineate a key feature underlying allosteric communication between the agonist-binding extracellular and channel-gating transmembrane domains. Extensive mutagenesis at this inter-domain interface re-affirms a critical energetically coupled role for the principal α subunit β1-β2 and M2-M3 loops, with agonist binding re-positioning a key β1-β2 glutamate/valine to facilitate the outward motions of a conserved M2-M3 proline to open the channel gate. Notably, the analogous structures in non-α subunits adopt a locally active-like conformation in the apo state even though each L9' hydrophobic gate residue in each pore-lining M2 α-helix is closed. Agonist binding releases local conformational heterogeneity transitioning all five subunits into a conformationally symmetric open state. A release of conformational heterogeneity provides a framework for understanding allosteric communication in pentameric ligand-gated ion channels.
MeSH term(s)	Receptors, Nicotinic/genetics ; Receptors, Nicotinic/metabolism ; Ion Channel Gating/physiology ; Molecular Conformation ; Receptors, Cholinergic/metabolism ; Muscles/metabolism
Chemical Substances	Receptors, Nicotinic ; Receptors, Cholinergic
Language	English
Publishing date	2024-02-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46028-x
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Article ; Online: Author Correction: Ion channels as lipid sensors: from structures to mechanisms.

Thompson, Mackenzie J / Baenziger, John E

Nature chemical biology

2020 Volume 17, Issue 2, Page(s) 229

Language	English
Publishing date	2020-12-10
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-020-00722-1
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Article ; Online: Structural basis for the modulation of pentameric ligand-gated ion channel function by lipids.

Thompson, Mackenzie J / Baenziger, John E

Biochimica et biophysica acta. Biomembranes

2020 Volume 1862, Issue 9, Page(s) 183304

Abstract: Pentameric ligand-gated ion channels (pLGICs) play a central role in synaptic communication and are implicated in a plethora of neurological disorders leading to human disease. Membrane lipids are known to modulate pLGIC function, but the mechanisms ... ...

Abstract	Pentameric ligand-gated ion channels (pLGICs) play a central role in synaptic communication and are implicated in a plethora of neurological disorders leading to human disease. Membrane lipids are known to modulate pLGIC function, but the mechanisms underlying their effects are poorly understood. Recent structures reveal sites for the binding of membrane lipids to pLGICs, thus providing a structural basis for interpreting functional data on pLGIC-lipid interactions. Here, we review the literature describing the known functional effects of membrane lipids on different members of the pLGIC superfamily and highlight pLGIC structures that exhibit bound lipids. We discuss new insight into the mechanisms of pLGIC-lipid interactions that has been derived from these recent structures.
MeSH term(s)	Binding Sites ; Humans ; Ligand-Gated Ion Channels/chemistry ; Ligand-Gated Ion Channels/genetics ; Lipids/chemistry ; Lipids/genetics ; Membrane Lipids/chemistry ; Membrane Lipids/genetics ; Models, Molecular ; Protein Structure, Quaternary ; Synapses/genetics ; Synapses/metabolism
Chemical Substances	Ligand-Gated Ion Channels ; Lipids ; Membrane Lipids
Language	English
Publishing date	2020-04-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	60-7
ISSN	1879-2642 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2642 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamem.2020.183304
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Article ; Online: Ion channels as lipid sensors: from structures to mechanisms.

Thompson, Mackenzie J / Baenziger, John E

Nature chemical biology

2020 Volume 16, Issue 12, Page(s) 1331–1342

Abstract: Ion channels play critical roles in cellular function by facilitating the flow of ions across the membrane in response to chemical or mechanical stimuli. Ion channels operate in a lipid bilayer, which can modulate or define their function. Recent ... ...

Abstract	Ion channels play critical roles in cellular function by facilitating the flow of ions across the membrane in response to chemical or mechanical stimuli. Ion channels operate in a lipid bilayer, which can modulate or define their function. Recent technical advancements have led to the solution of numerous ion channel structures solubilized in detergent and/or reconstituted into lipid bilayers, thus providing unprecedented insight into the mechanisms underlying ion channel-lipid interactions. Here, we describe how ion channel structures have evolved to respond to both lipid modulators and lipid activators to control the electrical activities of cells, highlighting diverse mechanisms and common themes.
MeSH term(s)	Animals ; Binding Sites ; Cell Communication ; Cell Membrane/chemistry ; Cell Membrane/metabolism ; Eukaryotic Cells/chemistry ; Eukaryotic Cells/metabolism ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/chemistry ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism ; Humans ; Lipid Bilayers/chemistry ; Lipid Bilayers/metabolism ; Mammals ; Models, Molecular ; Phosphatidylinositol Phosphates/metabolism ; Potassium Channels, Tandem Pore Domain/chemistry ; Potassium Channels, Tandem Pore Domain/genetics ; Potassium Channels, Tandem Pore Domain/metabolism ; Potassium Channels, Voltage-Gated/chemistry ; Potassium Channels, Voltage-Gated/genetics ; Potassium Channels, Voltage-Gated/metabolism ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Signal Transduction
Chemical Substances	G Protein-Coupled Inwardly-Rectifying Potassium Channels ; Lipid Bilayers ; Phosphatidylinositol Phosphates ; Potassium Channels, Tandem Pore Domain ; Potassium Channels, Voltage-Gated
Language	English
Publishing date	2020-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-020-00693-3
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Article: IUPAB 2021 Symposium 13: ion channels and membrane transporters.

Baenziger, John E / Ananchenko, Anna / Hussein, Toka O K / Mody, Deepansh

Biophysical reviews

2021 Volume 13, Issue 6, Page(s) 871–873

Language	English
Publishing date	2021-11-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2486483-3
ISSN	1867-2469 ; 1867-2450
ISSN (online)	1867-2469
ISSN	1867-2450
DOI	10.1007/s12551-021-00874-x
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Article ; Online: The functional role of the αM4 transmembrane helix in the muscle nicotinic acetylcholine receptor probed through mutagenesis and coevolutionary analyses.

Thompson, Mackenzie J / Domville, Jaimee A / Baenziger, John E

The Journal of biological chemistry

2020 Volume 295, Issue 32, Page(s) 11056–11067

Abstract: The activity of the muscle- ... ...

Abstract	The activity of the muscle-type
MeSH term(s)	Amino Acid Substitution ; Animals ; Biological Evolution ; Hydrophobic and Hydrophilic Interactions ; Ion Channel Gating ; Lipids/analysis ; Models, Molecular ; Muscles/metabolism ; Mutagenesis ; Protein Conformation ; Receptors, Nicotinic/chemistry ; Receptors, Nicotinic/genetics ; Receptors, Nicotinic/metabolism ; Torpedo
Chemical Substances	Lipids ; Receptors, Nicotinic
Language	English
Publishing date	2020-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA120.013751
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Article ; Online: An allosteric link connecting the lipid-protein interface to the gating of the nicotinic acetylcholine receptor.

Domville, Jaimee A / Baenziger, John E

Scientific reports

2018 Volume 8, Issue 1, Page(s) 3898

Abstract: The mechanisms underlying lipid-sensing by membrane proteins is of considerable biological importance. A unifying mechanistic question is how a change in structure at the lipid-protein interface is translated through the transmembrane domain to influence ...

Abstract	The mechanisms underlying lipid-sensing by membrane proteins is of considerable biological importance. A unifying mechanistic question is how a change in structure at the lipid-protein interface is translated through the transmembrane domain to influence structures critical to protein function. Gating of the nicotinic acetylcholine receptor (nAChR) is sensitive to its lipid environment. To understand how changes at the lipid-protein interface influence gating, we examined how a mutation at position 418 on the lipid-facing surface of the outer most M4 transmembrane α-helix alters the energetic couplings between M4 and the remainder of the transmembrane domain. Human muscle nAChR is sensitive to mutations at position 418, with the Cys-to-Trp mutation resulting in a 16-fold potentiation in function that leads to a congenital myasthenic syndrome. Energetic coupling between M4 and the Cys-loop, a key structure implicated in gating, do not change with C418W. Instead, Trp418 and an adjacent residue couple energetically with residues on the M1 transmembrane α-helix, leading to a reorientation of M1 that stabilizes the open state. We thus identify an allosteric link connecting the lipid-protein interface of the nAChR to altered channel function.
MeSH term(s)	Allosteric Regulation ; Allosteric Site/genetics ; Cell Membrane/metabolism ; Cell Membrane/physiology ; Humans ; Ion Channel Gating/physiology ; Lipid-Linked Proteins/physiology ; Lipids/chemistry ; Lipids/physiology ; Models, Molecular ; Protein Conformation ; Protein Domains ; Receptors, Nicotinic/genetics ; Receptors, Nicotinic/metabolism ; Receptors, Nicotinic/ultrastructure ; Signal Transduction
Chemical Substances	Lipid-Linked Proteins ; Lipids ; Receptors, Nicotinic
Language	English
Publishing date	2018-03-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-22150-x
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Article ; Online: Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels.

Ananchenko, Anna / Hussein, Toka O K / Mody, Deepansh / Thompson, Mackenzie J / Baenziger, John E

Biomolecules

2022 Volume 12, Issue 6

Abstract: Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids ...

Abstract	Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function and may help shape synaptic communication. Increasing structural and biophysical data reveal sites for lipid binding to pLGICs. Here, we update our evolving understanding of pLGIC-lipid interactions highlighting newly identified modes of lipid binding along with the mechanistic understanding derived from the new structural data.
MeSH term(s)	Binding Sites ; Ligand-Gated Ion Channels/chemistry ; Ligand-Gated Ion Channels/metabolism ; Lipids
Chemical Substances	Ligand-Gated Ion Channels ; Lipids
Language	English
Publishing date	2022-06-10
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12060814
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Article: Functional characterization of two prokaryotic pentameric ligand-gated ion channel chimeras - role of the GLIC transmembrane domain in proton sensing.

Hénault, Camille M / Baenziger, John E

Biochimica et biophysica acta. Biomembranes

2016 Volume 1859, Issue 2, Page(s) 218–227

Abstract: With the long-term goal of using a chimeric approach to dissect the distinct lipid sensitivities and thermal stabilities of the pentameric ligand-gated ion channels (pLGIC), GLIC and ELIC, we constructed chimeras by cross-combining their extracellular ( ... ...

Abstract	With the long-term goal of using a chimeric approach to dissect the distinct lipid sensitivities and thermal stabilities of the pentameric ligand-gated ion channels (pLGIC), GLIC and ELIC, we constructed chimeras by cross-combining their extracellular (ECD) and transmembrane (TMD) domains. As expected, the chimera formed between GLIC-ECD and ELIC-TMD (GE) responded to protons, the agonist for GLIC, but not cysteamine, the agonist for ELIC, although GE exhibited a 25-fold decrease in proton-sensitivity relative to wild type. The chimera formed between ELIC-ECD and the GLIC-TMD (EG) was usually toxic, unless it contained a pore-lining Ile9'Ala gain-of-function mutation. No significant improvements in expression/toxicity were observed with extensive loop substitutions at the ECD/TMD interface. Surprisingly, oocytes expressing EG-I9'A responded to both the ELIC agonist, cysteamine and the GLIC agonist, protons - the latter at pH values ≤4.0. The cysteamine- and proton-induced currents in EG-I9'A were inhibited by the GLIC TMD pore blocker, amantadine. The cysteamine-induced response of EG-I9'A was also inhibited by protons at pH values down to 4.5, but potentiated at lower pH values. Proton-induced gating at low pH was not abolished by mutation of an intramembrane histidine residue previously implicated in GLIC TMD function. We show that the TMD plays a major role governing the thermal stability of a pLGIC, and identify three distinct mechanisms by which agonists and protons influence the gating of the EG chimera. A structural basis for the impaired function of GE is suggested.
MeSH term(s)	Animals ; Chimera/metabolism ; Crystallography, X-Ray/methods ; Cysteamine/metabolism ; Histidine/metabolism ; Ion Channel Gating/physiology ; Ligand-Gated Ion Channels/metabolism ; Ligands ; Models, Molecular ; Mutation/genetics ; Oocytes/metabolism ; Prokaryotic Cells/metabolism ; Protein Domains/physiology ; Protons ; Xenopus laevis/metabolism
Chemical Substances	Ligand-Gated Ion Channels ; Ligands ; Protons ; Histidine (4QD397987E) ; Cysteamine (5UX2SD1KE2)
Language	English
Publishing date	2016-11-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0005-2736 ; 0006-3002 ; 0005-2728 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0005-2736 ; 0006-3002 ; 0005-2728 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamem.2016.11.006
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