Structure-Based Engineering of Lithium-Transport Capacity in an Archaeal Sodium–Calcium Exchanger

Members of the Ca2+/cation exchanger superfamily (Ca2+/CA) share structural similarities (including highly conserved ion-coordinating residues) while exhibiting differential selectivity for Ca2+, Na+, H+, K+, and Li+. The archaeal Na+/Ca2+ exchanger (NCX_Mj) and its mammalian orthologs are highly selective for Na+, whereas the mitochondrial ortholog (NCLX) can transport either Li+ or Na+ in exchange with Ca2+. Here, structure-based replacement of ion-coordinating residues in NCX_Mj resulted in a capacity for transporting either Na+ or Li+, similar to the case for NCLX. This engineered protein may serve as a model for elucidating the mechanisms underlying ion selectivity and ion-coupled alternating access in NCX and similar proteins.