INVESTIGADORES
ELGOYHEN Ana Belen
congresos y reuniones científicas
Título:
TRACKING THE MOLECULAR EVOLUTION OF CALCIUM PERMEABILITY IN A NICOTINIC ACETYLCHOLINE RECEPTOR
Autor/es:
ELGOYHEN AB; LIPOVSEK M
Reunión:
Congreso; Nicotinic Acetylcholine Receptors 2014, Wellcome Trust Scientific Meetings; 2014
Institución organizadora:
Wellcome Trust
Resumen:
Nicotinic
acetylcholine receptors are a family of ligand-gated non-selective cationic
channels that participate in fundamental physiological processes both at the
central and the peripheral nervous system. The extent of calcium entry through
ligand-gated ion channels defines their distinct functions. The á9á10 nicotinic
cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of
the family since it shows differences in the extent of calcium permeability
across species. In particular, mammalian á9á10 receptors are among the
ligand-gated ion channels which exhibit the highest calcium selectivity. This
evolutionarily-acquired adaptation provides the unique opportunity of studying
how protein function was shaped along evolutionary history, by identifying
amino acids that were positively selected by nature. 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 evolution events that yielded a high
calcium permeable nicotinic á9á10 mammalian receptor. Only three specific amino
acid substitutions in the á9 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 were selected amongst other
seemingly neutral changes that provided the background structure necessary for
high calcium permeability. Thus, the consequences of a given substitution
greatly depend on the overall sequence (and hence structure) of the protein, a
phenomena referred to as epistasis These results highlight the importance of
tracking evolutionarily-acquired changes in protein sequence underlying
fundamental functional properties of ligand-gated ion channels.