Tracking the Molecular Evolution of Calcium Permeability in a Nicotinic Acetylcholine Receptor
| Autor: | Marcela Lipovsek, Neil S. Millar, Angélica Fierro, Ana Belén Elgoyhen, Edwin G. Pérez, Juan Carlos Boffi, Eleonora Katz, Paul A. Fuchs |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
calcium permeability
Receptors Nicotinic Xenopus laevis 0302 clinical medicine Protein structure Nicotinic Agonists Cells Cultured Calcium signaling HEARING 0303 health sciences Nicotinic acetylcholine receptor Nicotinic agonist Biochemistry NICOTINIC RECEPTORS CIENCIAS NATURALES Y EXACTAS Acetylcholine medicine.drug nicotinic receptors Otras Ciencias Biológicas Molecular Sequence Data chemistry.chemical_element Biology Calcium Molecular Dynamics Simulation Permeability Ciencias Biológicas Avian Proteins Evolution Molecular 03 medical and health sciences Genetics medicine Animals Humans Amino Acid Sequence Calcium Signaling Molecular Biology Ecology Evolution Behavior and Systematics Ion channel Discoveries 030304 developmental biology Acetylcholine receptor molecular evolution Cell Membrane CALCIUM PERMEABILITY MOLECULAR EVOLUTION Rats chemistry hearing Biophysics Chickens 030217 neurology & neurosurgery |
| Zdroj: | Molecular Biology and Evolution |
| ISSN: | 1537-1719 0737-4038 |
| Popis: | Nicotinic acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species. In particular, mammalian α9α10 receptors are among the ligand-gated ion channels which exhibit the highest calcium selectivity. This acquired differential property provides the unique opportunity of studying how protein function was shaped along evolutionary history, by tracking its evolutionary record and experimentally defining the amino acid changes involved. We have applied a molecular evolution approach of ancestral sequence reconstruction, together with molecular dynamics simulations and an evolutionary-based mutagenesis strategy, in order to trace the molecular events that yielded a high calcium permeable nicotinic α9α10 mammalian receptor. Only three specific amino acid substitutions in the α9 subunit were directly involved. These are located at the extracellular vestibule and at the exit of the channel pore and not at the transmembrane region 2 of the protein as previously thought. Moreover, we show that these three critical substitutions only increase calcium permeability in the context of the mammalian but not the avian receptor, stressing the relevance of overall protein structure on defining functional properties. These results highlight the importance of tracking evolutionarily acquired changes in protein sequence underlying fundamental functional properties of ligand-gated ion channels. Fil: Lipovsek, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina Fil: Fierro, Angélica. Pontificia Universidad Católica de Chile; Chile Fil: Perez, Edwin G.. Pontificia Universidad Católica de Chile; Chile Fil: Boffi, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina Fil: Millar, Neil S.. University College London; Estados Unidos Fil: Fuchs, Paul A.. University Johns Hopkins; Estados Unidos Fil: Katz, Eleonora. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina Fil: Elgoyhen, Ana Belen. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|