Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function

Nicotinic acetylcholine receptors can be assembled from either homomeric or heteromeric pentameric subunit combinations. At the interface of the extracellular domains of adjacent subunits lies the acetylcholine binding site, composed of a principal component provided by one subunit and a complementa...

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Autores principales: Boffi, J.C., Marcovich, I., Gill-Thind, J.K., Corradi, J., Collins, T., Lipovsek, M.M., Moglie, M., Plazas, P.V., Craig, P.O., Millar, N.S., Bouzat, C., Elgoyhen, A.B.
Formato: JOUR
Materias:
nicotinic receptor
receptor subunit
acetylcholine
protein subunit
animal cell
Article
binding site
controlled study
molecular docking
molecular model
nonhuman
priority journal
protein domain
rat
receptor binding
site directed mutagenesis
amino acid sequence
animal
chemistry
chicken
genetics
metabolism
mutation
protein secondary structure
structural homology
structure activity relation
Acetylcholine
Amino Acid Sequence
Animals
Binding Sites
Chickens
Molecular Docking Simulation
Mutation
Protein Structure, Secondary
Protein Subunits
Rats
Receptors, Nicotinic
Structural Homology, Protein
Structure-Activity Relationship
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_0026895X_v91_n3_p250_Boffi
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
id todo:paper_0026895X_v91_n3_p250_Boffi
record_format dspace
spelling todo:paper_0026895X_v91_n3_p250_Boffi2023-10-03T14:37:14Z Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function Boffi, J.C. Marcovich, I. Gill-Thind, J.K. Corradi, J. Collins, T. Lipovsek, M.M. Moglie, M. Plazas, P.V. Craig, P.O. Millar, N.S. Bouzat, C. Elgoyhen, A.B. nicotinic receptor receptor subunit acetylcholine nicotinic receptor protein subunit animal cell Article binding site controlled study molecular docking molecular model nonhuman priority journal protein domain rat receptor binding site directed mutagenesis amino acid sequence animal chemistry chicken genetics metabolism mutation protein secondary structure protein subunit structural homology structure activity relation Acetylcholine Amino Acid Sequence Animals Binding Sites Chickens Molecular Docking Simulation Mutation Protein Structure, Secondary Protein Subunits Rats Receptors, Nicotinic Structural Homology, Protein Structure-Activity Relationship Nicotinic acetylcholine receptors can be assembled from either homomeric or heteromeric pentameric subunit combinations. At the interface of the extracellular domains of adjacent subunits lies the acetylcholine binding site, composed of a principal component provided by one subunit and a complementary component of the adjacent subunit. Compared with neuronal nicotinic acetylcholine cholinergic receptors (nAChRs) assembled from α and β subunits, the α9α10 receptor is an atypical member of the family. It is a heteromeric receptor composed only of α subunits. Whereas mammalian α9 subunits can form functional homomeric α9 receptors, α10 subunits do not generate functional channels when expressed heterologously. Hence, it has been proposed that α10 might serve as a structural subunit, much like a β subunit of heteromeric nAChRs, providing only complementary components to the agonist binding site. Here, we have made use of site-directed mutagenesis to examine the contribution of subunit interface domains to α9α10 receptors by a combination of electrophysiological and radioligand binding studies. Characterization of receptors containing Y190T mutations revealed unexpectedly that both α9 and α10 subunits equally contribute to the principal components of the α9α10 nAChR. In addition, we have shown that the introduction of a W55T mutation impairs receptor binding and function in the rat α9 subunit but not in the α10 subunit, indicating that the contribution of α9 and α10 subunits to complementary components of the ligand-binding site is non-equivalent. We conclude that this asymmetry, which is supported by molecular docking studies, results from adaptive amino acid changes acquired only during the evolution of mammalian α10 subunits. Copyright © 2017 by The Author(s). Fil:Boffi, J.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Lipovsek, M.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Moglie, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Plazas, P.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_0026895X_v91_n3_p250_Boffi
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-134
collection Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic nicotinic receptor
receptor subunit
acetylcholine
nicotinic receptor
protein subunit
animal cell
Article
binding site
controlled study
molecular docking
molecular model
nonhuman
priority journal
protein domain
rat
receptor binding
site directed mutagenesis
amino acid sequence
animal
chemistry
chicken
genetics
metabolism
mutation
protein secondary structure
protein subunit
structural homology
structure activity relation
Acetylcholine
Amino Acid Sequence
Animals
Binding Sites
Chickens
Molecular Docking Simulation
Mutation
Protein Structure, Secondary
Protein Subunits
Rats
Receptors, Nicotinic
Structural Homology, Protein
Structure-Activity Relationship
spellingShingle nicotinic receptor
receptor subunit
acetylcholine
nicotinic receptor
protein subunit
animal cell
Article
binding site
controlled study
molecular docking
molecular model
nonhuman
priority journal
protein domain
rat
receptor binding
site directed mutagenesis
amino acid sequence
animal
chemistry
chicken
genetics
metabolism
mutation
protein secondary structure
protein subunit
structural homology
structure activity relation
Acetylcholine
Amino Acid Sequence
Animals
Binding Sites
Chickens
Molecular Docking Simulation
Mutation
Protein Structure, Secondary
Protein Subunits
Rats
Receptors, Nicotinic
Structural Homology, Protein
Structure-Activity Relationship
Boffi, J.C.
Marcovich, I.
Gill-Thind, J.K.
Corradi, J.
Collins, T.
Lipovsek, M.M.
Moglie, M.
Plazas, P.V.
Craig, P.O.
Millar, N.S.
Bouzat, C.
Elgoyhen, A.B.
Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function
topic_facet nicotinic receptor
receptor subunit
acetylcholine
nicotinic receptor
protein subunit
animal cell
Article
binding site
controlled study
molecular docking
molecular model
nonhuman
priority journal
protein domain
rat
receptor binding
site directed mutagenesis
amino acid sequence
animal
chemistry
chicken
genetics
metabolism
mutation
protein secondary structure
protein subunit
structural homology
structure activity relation
Acetylcholine
Amino Acid Sequence
Animals
Binding Sites
Chickens
Molecular Docking Simulation
Mutation
Protein Structure, Secondary
Protein Subunits
Rats
Receptors, Nicotinic
Structural Homology, Protein
Structure-Activity Relationship
description Nicotinic acetylcholine receptors can be assembled from either homomeric or heteromeric pentameric subunit combinations. At the interface of the extracellular domains of adjacent subunits lies the acetylcholine binding site, composed of a principal component provided by one subunit and a complementary component of the adjacent subunit. Compared with neuronal nicotinic acetylcholine cholinergic receptors (nAChRs) assembled from α and β subunits, the α9α10 receptor is an atypical member of the family. It is a heteromeric receptor composed only of α subunits. Whereas mammalian α9 subunits can form functional homomeric α9 receptors, α10 subunits do not generate functional channels when expressed heterologously. Hence, it has been proposed that α10 might serve as a structural subunit, much like a β subunit of heteromeric nAChRs, providing only complementary components to the agonist binding site. Here, we have made use of site-directed mutagenesis to examine the contribution of subunit interface domains to α9α10 receptors by a combination of electrophysiological and radioligand binding studies. Characterization of receptors containing Y190T mutations revealed unexpectedly that both α9 and α10 subunits equally contribute to the principal components of the α9α10 nAChR. In addition, we have shown that the introduction of a W55T mutation impairs receptor binding and function in the rat α9 subunit but not in the α10 subunit, indicating that the contribution of α9 and α10 subunits to complementary components of the ligand-binding site is non-equivalent. We conclude that this asymmetry, which is supported by molecular docking studies, results from adaptive amino acid changes acquired only during the evolution of mammalian α10 subunits. Copyright © 2017 by The Author(s).
format JOUR
author Boffi, J.C.
Marcovich, I.
Gill-Thind, J.K.
Corradi, J.
Collins, T.
Lipovsek, M.M.
Moglie, M.
Plazas, P.V.
Craig, P.O.
Millar, N.S.
Bouzat, C.
Elgoyhen, A.B.
author_facet Boffi, J.C.
Marcovich, I.
Gill-Thind, J.K.
Corradi, J.
Collins, T.
Lipovsek, M.M.
Moglie, M.
Plazas, P.V.
Craig, P.O.
Millar, N.S.
Bouzat, C.
Elgoyhen, A.B.
author_sort Boffi, J.C.
title Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function
title_short Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function
title_full Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function
title_fullStr Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function
title_full_unstemmed Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function
title_sort differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function
url http://hdl.handle.net/20.500.12110/paper_0026895X_v91_n3_p250_Boffi
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