Aromaticity at the Water-Hydrocarbon Core Interface of the Membrane: Consequences on the Nicotinic Acetylcholine Receptor

Lizardi-Ortiz, José E.; Hyzinski‐García, María C.; Fernández-Gerena, José L.; Osorio-Martínez, Karen M.; Velázquez-Rivera, Eric; Valle-Avilés, Félix L.; Lasalde‐Dominicci, José A.

doi:10.4161/chan.2.3.6385

Cited by 3 publications

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“…; Wallace and Janes ; Lizardi‐Ortiz et al . ). We reviewed the validity of these observations for the annotated human proteome, and for a set of 220 synaptic membrane proteins, and we found that the accumulation of tyrosine and tryptophan was in fact a global feature of their transmembrane domains (Table ).…”

Section: Discussionmentioning

confidence: 97%

Membrane protein oxidation determines neuronal degeneration

Hajieva

Bayatti

Granold

et al. 2015

Journal of Neurochemistry

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Oxidative stress is an early hallmark in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. However, the critical biochemical effector mechanisms of oxidative neurotoxicity have remained surprisingly elusive. In screening various peroxides and potential substrates of oxidation for their effect on neuronal survival, we observed that intramembrane compounds were significantly more active than aqueous or amphiphilic compounds. To better understand this result, we synthesized a series of competitive and site-specific membrane protein oxidation inhibitors termed aminoacyllipids, whose structures were designed on the basis of amino acids frequently found at the protein-lipid interface of synaptic membrane proteins. Investigating the aminoacyllipids in primary neuronal culture, we found that the targeted protection of transmembrane tyrosine and tryptophan residues was sufficient to prevent neurotoxicity evoked by hydroperoxides, kainic acid, glutathione-depleting drugs, and certain amyloidogenic peptides, but ineffective against non-oxidative inducers of apoptosis such as sphingosine or Akt kinase inhibitors. Thus, the oxidative component of different neurotoxins appears to converge on neuronal membrane proteins, irrespective of the primary mechanism of cellular oxidant generation. Our results indicate the existence of a oneelectron redox cycle based on membrane protein aromatic surface amino acids, whose disturbance or overload leads to excessive membrane protein oxidation and neuronal death. However, comparative investigations of postmortem biomarker oxidation also have inherent limitations. In general, a chemical rationale for the observed structural specificity, if detected, can rarely be assigned. Moreover, it is usually impossible to assess through mere comparison the causal role of an oxidative event in disease progression. A causal Received March 18, 2014; revised manuscript received October 10, 2014; accepted October 24, 2014. Address correspondence and reprint requests to Parvana Hajieva and Christian Behl, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55099 Mainz, Germany. E-mail: hajieva@uni-mainz.de and cbehl@uni-mainz.de 1 Present address: Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield S10 2HQ, UK.Abbreviations used: 6-DCFA, 6-carboxy-2 0 ,7 0 -dichlorodihydrofluorescein diacetate bisacetoxymethyl ester; BSO, buthionine sulfoximine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

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Section: Discussionmentioning

confidence: 97%

Membrane protein oxidation determines neuronal degeneration

Hajieva

Bayatti

Granold

et al. 2015

Journal of Neurochemistry

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An allosteric link connecting the lipid-protein interface to the gating of the nicotinic acetylcholine receptor

Domville

Baenziger

2018

Sci Rep

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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.

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Mapping the Allosteric Pathway Leading from a Mutation in the Nicotinic Acetylcholine Receptor to a Congenital Myasthenic Syndrome

Domville¹

2017

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Aromaticity at the Water-Hydrocarbon Core Interface of the Membrane: Consequences on the Nicotinic Acetylcholine Receptor

Cited by 3 publications

References 50 publications

Membrane protein oxidation determines neuronal degeneration

Membrane protein oxidation determines neuronal degeneration

An allosteric link connecting the lipid-protein interface to the gating of the nicotinic acetylcholine receptor

Mapping the Allosteric Pathway Leading from a Mutation in the Nicotinic Acetylcholine Receptor to a Congenital Myasthenic Syndrome

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