Anionic Lipids Allosterically Modulate Multiple Nicotinic Acetylcholine Receptor Conformational Equilibria

daCosta, Corrie J.B.; Medaglia, Sarah A.; Lavigne, Nadine; Wang, Shuzhi; Carswell, Casey L.; Baenziger, John E.

doi:10.1074/jbc.m109.048280

Cited by 60 publications

(54 citation statements)

References 47 publications

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“…The lipid composition of the membrane is a key determinant of the allosteric modulation of receptor function for some receptors (37,39,53). However, in the case of EnvZ, we observed no significant differences in enzymatic activity between the physiological E. coli lipids and the nonbacterial phospholipid DOPC.…”

Section: Discussion Lipids As Allosteric Modulators Of Membrane Protecontrasting

confidence: 51%

Lipid-Mediated Regulation of Embedded Receptor Kinases via Parallel Allosteric Relays

Ghosh

Wang

Ramesh

et al. 2017

Biophysical Journal

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Membrane-anchored receptors are essential cellular signaling elements for stimulus sensing, propagation, and transmission inside cells. However, the contributions of lipid interactions to the function and dynamics of embedded receptor kinases have not been described in detail. In this study, we used amide hydrogen/deuterium exchange mass spectrometry, a sensitive biophysical approach, to probe the dynamics of a membrane-embedded receptor kinase, EnvZ, together with functional assays to describe the role of lipids in receptor kinase function. Our results reveal that lipids play an important role in regulating receptor function through interactions with transmembrane segments, as well as through peripheral interactions with nonembedded domains. Specifically, the lipid membrane allosterically modulates the activity of the embedded kinase by altering the dynamics of a glycine-rich motif that is critical for phosphotransfer from ATP. This allostery in EnvZ is independent of membrane composition and involves direct interactions with transmembrane and periplasmic segments, as well as peripheral interactions with nonembedded domains of the protein. In the absence of the membrane-spanning regions, lipid allostery is propagated entirely through peripheral interactions. Whereas lipid allostery impacts the phosphotransferase function of the kinase, extracellular stimulus recognition is mediated via a four-helix bundle subdomain located in the cytoplasm, which functions as the osmosensing core through osmolality-dependent helical stabilization. Our findings emphasize the functional modularity in a membrane-embedded kinase, separated into membrane association, phosphotransferase function, and stimulus recognition. These components are integrated through long-range communication relays, with lipids playing an essential role in regulation.

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Section: Discussion Lipids As Allosteric Modulators Of Membrane Protecontrasting

confidence: 51%

Lipid-Mediated Regulation of Embedded Receptor Kinases via Parallel Allosteric Relays

Ghosh

Wang

Ramesh

et al. 2017

Biophysical Journal

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“…In fact, these factors have been shown to affect the conformational dynamics of BtuB (the Escherichia coli outer-membrane transporter for vitamin B 12 ) (33)(34)(35) and the kinetics of the photocycle in bacteriorhodopsin (36), for example. In addition, of particular relevance to this article, the effect of membrane lipids on the relative occupancies of the closed, open and desensitized states of the AChR from Torpedo's electric organ has been well documented (3,37,38). Alternatively, it may well be that only one conformation of ELIC crystallizes under the tested conditions, in which case all efforts to crystallize specific functional states of the channel by appropriately tilting the free-energy landscape would be futile.…”

Section: Discussionmentioning

confidence: 99%

Mutations that stabilize the open state of the Erwinia chrisanthemi ligand-gated ion channel fail to change the conformation of the pore domain in crystals

González-Gutiérrez

Lukk

Agarwal

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The determination of structural models of the various stable states of an ion channel is a key step toward the characterization of its conformational dynamics. In the case of nicotinic-type receptors, different structures have been solved but, thus far, these different models have been obtained from different members of the superfamily. In the case of the bacterial member ELIC, a cysteamine-gated channel from Erwinia chrisanthemi, a structural model of the protein in the absence of activating ligand (and thus, conceivably corresponding to the closed state of this channel) has been previously generated. In this article, electrophysiological characterization of ELIC mutants allowed us to identify pore mutations that slow down the time course of desensitization to the extent that the channel seems not to desensitize at all for the duration of the agonist applications (>20 min). Thus, it seems reasonable to conclude that the probability of ELIC occupying the closed state is much lower for the ligand-bound mutants than for the unliganded wild-type channel. To gain insight into the conformation adopted by ELIC under these conditions, we solved the crystal structures of two of these mutants in the presence of a concentration of cysteamine that elicits an intracluster open probability of >0.9. Curiously, the obtained structural models turned out to be nearly indistinguishable from the model of the wild-type channel in the absence of bound agonist. Overall, our findings bring to light the limited power of functional studies in intact membranes when it comes to inferring the functional state of a channel in a crystal, at least in the case of the nicotinicreceptor superfamily.electrophysiology | structure-function T he use of bacterial and archaeal ion channels as models of the structure and function of their eukaryotic counterparts has become one of the mainstays of ion-channel biophysics. It seems to us that this practice is particularly well justified whenever the use of noneukaryotic channels facilitates experiments that are otherwise too difficult or too cumbersome to perform. A clear case in point is the determination of structural models of these membrane proteins using X-ray crystallography.One of the main goals of direct structural approaches as applied to ion channels is to determine what these proteins look like in their different functional states. Assuming that all of these conformations can form well-diffracting crystals, the problem is reduced to finding the conditions under which the occupancy of each particular state is maximized. In general, for well-characterized ion channels, the experimental maneuvers that are needed to favor or disfavor at least some of these different conformations are known. For example, in the case of (wild-type) neurotransmitter-gated channels, the binding of the natural neurotransmitter strongly stabilizes the desensitized state (e.g., ref. 1), whereas the absence of neurotransmitter or the binding of a competitive antagonist keeps the channel mostly closed (2, 3). Similarly, mut...

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“…More specific examples include neuroactive steroids acting at the GABA A receptor (Olsen and Sapp, 1995), L-amino acids acting at the extracellular calcium-sensing receptor (Conigrave et al, 2000), and others (Christopoulos, 2002;May et al, 2007). Furthermore, membrane lipids may modify nicotinic receptors allosterically, changing the effects of other allosteric agents (daCosta et al, 2009). Moreover, there are a number of pathophysiological conditions that may be mediated by endogenous substances acting allosterically at some receptors (May et al, 2007).…”

Section: Classification Of Endogenous Allosteric Ligandsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

et al. 2014

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Anionic Lipids Allosterically Modulate Multiple Nicotinic Acetylcholine Receptor Conformational Equilibria

Cited by 60 publications

References 47 publications

Lipid-Mediated Regulation of Embedded Receptor Kinases via Parallel Allosteric Relays

Lipid-Mediated Regulation of Embedded Receptor Kinases via Parallel Allosteric Relays

Mutations that stabilize the open state of the Erwinia chrisanthemi ligand-gated ion channel fail to change the conformation of the pore domain in crystals

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

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