The roles of aromatic residues in the glycine receptor transmembrane domain

Tang, Bijun; Lummis, Sarah C. R.

doi:10.1186/s12868-018-0454-8

Cited by 17 publications

(33 citation statements)

References 27 publications

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“…Previous studies with other pLGICs have highlighted a role for the M4 C terminus in function, possibly through interactions with the Cys-loop (36,38,39,45). In contrast, Ala mutations of most residues at the aM4 C terminus that could interact with the Cys-loop or other structures in the ECD have little effect on the measured EC 50 values, as discussed above, suggesting that such interactions are not critical in the muscle nAChR.…”

Section: The Am4 C Terminusmentioning

confidence: 76%

“…A tight, complementary aromatic interface between M4 and M1/M3 is not only essential for both folding and function but also leads to tighter interactions (than those in ELIC) that render GLIC functionally insensitive to its surrounding membrane environment (30,44). A complex network of interacting aromatic residues at the M4-M1/M3 interface is also observed in anionselective pLGICs (59), with Ala substitutions of aromatic residues in these pLGICs generally leading to losses in function and/or expression (44,45).…”

Section: Discussionmentioning

confidence: 99%

“…To better understand lipid sensing, we and others have used Ala-scanning mutagenesis to identify residues in M4 that play an important role in function (36,39,(44)(45)(46)(47). Whereas these studies have been informative, they have all focused on homomeric pLGICs.…”

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confidence: 99%

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The functional role of the αM4 transmembrane helix in the muscle nicotinic acetylcholine receptor probed through mutagenesis and coevolutionary analyses

Thompson

Domville

Baenziger

2020

Journal of Biological Chemistry

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The activity of the muscle-type Torpedo nicotinic acetylcholine receptor (nAChR) is highly sensitive to lipids, but the underlying mechanisms remain poorly understood. The nAChR transmembrane α‑helix, M4, is positioned at the perimeter of each subunit in direct contact with lipids and likely plays a central role in lipid-sensing. To gain insight into the mechanisms underlying nAChR lipid-sensing, we use homology modeling, co-evolutionary analyses, site-directed mutagenesis and electrophysiology to examine the role of the α-subunit M4 (αM4) in the function of the adult muscle nAChR. Ala substitutions of most αM4 residues, including those in clusters of polar residues at both the N and C termini, and deletion of up to 11 C-terminal residues had little impact on the agonist-induced response. Even Ala substitutions of co-evolved pairs of residues at the interface between αM4 and the adjacent helices, αM1 and αM3, had little effect, although some impaired nAChR expression. On the other hand, Ala substitutions of Thr422 and Arg429 caused relatively large losses of function, suggesting functional roles for these specific residues. Ala substitutions of aromatic residues at the αM4-αM1/αM3 interface generally led to gains of function, as previously reported for the prokaryotic homolog, the Erwinia chrysanthemi ligand-gated ion channel (ELIC). The functional effects of individual Ala substitutions in αM4 were found to be additive, although not in a completely independent manner. Our results provide insight into the structural features of αM4 that are important. They also suggest how lipid dependent changes in αM4 structure may ultimately modify nAChR function.

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Section: The Am4 C Terminusmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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The functional role of the αM4 transmembrane helix in the muscle nicotinic acetylcholine receptor probed through mutagenesis and coevolutionary analyses

Thompson

Domville

Baenziger

2020

Journal of Biological Chemistry

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“…Following agonist binding an anticlockwise rotation around the pore axis is initiated thus leading to an anticlockwise rotation of the entire transmembrane domains of all five subunits (Du et al, 2015). The transmembrane domains represent α-helical elements with stacking interactions between aromatic residues localized in the same or adjacent helices (Haeger et al, 2010;James et al, 2013;Tang and Lummis, 2018). The intramembrane aromatic residues are important for pentameric assembly and ion channel function, e.g., allosteric modulation and interaction with lipids (Carswell et al, 2015;Sridhar et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease

Piro

Eckes

Kasaragod

et al. 2021

Front. Mol. Neurosci.

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Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC50 value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations.

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“…Second, these modules that have probably co-evolved for integrating multiple signals have acquired highly conserved aromatic residues that play critical and perhaps still not well-understood roles in both information transfer and processing [ 46 ]. For example, particular motifs formed between aromatic and charged residues (such as cation-π) mediate the communication between the allosteric modules or form the “ligand-binding pocket” in most of the membrane receptors [ 310 , 541 ] ( Figure 8 ).…”

Section: Evolution Of Informational Systems Across Scalesmentioning

confidence: 99%

Towards the Idea of Molecular Brains

Timsit

Sergeant-Perthuis

2021

IJMS

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How can single cells without nervous systems perform complex behaviours such as habituation, associative learning and decision making, which are considered the hallmark of animals with a brain? Are there molecular systems that underlie cognitive properties equivalent to those of the brain? This review follows the development of the idea of molecular brains from Darwin’s “root brain hypothesis”, through bacterial chemotaxis, to the recent discovery of neuron-like r-protein networks in the ribosome. By combining a structural biology view with a Bayesian brain approach, this review explores the evolutionary labyrinth of information processing systems across scales. Ribosomal protein networks open a window into what were probably the earliest signalling systems to emerge before the radiation of the three kingdoms. While ribosomal networks are characterised by long-lasting interactions between their protein nodes, cell signalling networks are essentially based on transient interactions. As a corollary, while signals propagated in persistent networks may be ephemeral, networks whose interactions are transient constrain signals diffusing into the cytoplasm to be durable in time, such as post-translational modifications of proteins or second messenger synthesis. The duration and nature of the signals, in turn, implies different mechanisms for the integration of multiple signals and decision making. Evolution then reinvented networks with persistent interactions with the development of nervous systems in metazoans. Ribosomal protein networks and simple nervous systems display architectural and functional analogies whose comparison could suggest scale invariance in information processing. At the molecular level, the significant complexification of eukaryotic ribosomal protein networks is associated with a burst in the acquisition of new conserved aromatic amino acids. Knowing that aromatic residues play a critical role in allosteric receptors and channels, this observation suggests a general role of π systems and their interactions with charged amino acids in multiple signal integration and information processing. We think that these findings may provide the molecular basis for designing future computers with organic processors.

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The roles of aromatic residues in the glycine receptor transmembrane domain

Cited by 17 publications

References 27 publications

The functional role of the αM4 transmembrane helix in the muscle nicotinic acetylcholine receptor probed through mutagenesis and coevolutionary analyses

The functional role of the αM4 transmembrane helix in the muscle nicotinic acetylcholine receptor probed through mutagenesis and coevolutionary analyses

Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease

Towards the Idea of Molecular Brains

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