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...
Guardado en:
| Autores principales: | , , , |
|---|---|
| Publicado: |
2017
|
| Materias: | |
| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0026895X_v91_n3_p250_Boffi http://hdl.handle.net/20.500.12110/paper_0026895X_v91_n3_p250_Boffi |
| Aporte de: |
| id |
paper:paper_0026895X_v91_n3_p250_Boffi |
|---|---|
| record_format |
dspace |
| spelling |
paper:paper_0026895X_v91_n3_p250_Boffi2023-06-08T14:53:58Z Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function Boffi, Juan Carlos Lipovsek, María Marcela Moglie, Marcelo Javier Plazas, Paola Viviana 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. 2017 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0026895X_v91_n3_p250_Boffi 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, Juan Carlos Lipovsek, María Marcela Moglie, Marcelo Javier Plazas, Paola Viviana 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). |
| author |
Boffi, Juan Carlos Lipovsek, María Marcela Moglie, Marcelo Javier Plazas, Paola Viviana |
| author_facet |
Boffi, Juan Carlos Lipovsek, María Marcela Moglie, Marcelo Javier Plazas, Paola Viviana |
| author_sort |
Boffi, Juan Carlos |
| 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 |
| publishDate |
2017 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0026895X_v91_n3_p250_Boffi http://hdl.handle.net/20.500.12110/paper_0026895X_v91_n3_p250_Boffi |
| work_keys_str_mv |
AT boffijuancarlos differentialcontributionofsubunitinterfacestoa9a10nicotinicacetylcholinereceptorfunction AT lipovsekmariamarcela differentialcontributionofsubunitinterfacestoa9a10nicotinicacetylcholinereceptorfunction AT mogliemarcelojavier differentialcontributionofsubunitinterfacestoa9a10nicotinicacetylcholinereceptorfunction AT plazaspaolaviviana differentialcontributionofsubunitinterfacestoa9a10nicotinicacetylcholinereceptorfunction |
| _version_ |
1768545727788613632 |