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

Members of the Ca(2+)/cation exchanger superfamily (Ca(2+)/CA) share structural similarities (including highly conserved ion-coordinating residues) while exhibiting differential selectivity for Ca(2+), Na(+), H(+), K(+), and Li(+). The archaeal Na(+)/Ca(2+) 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 Ca(2+). 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.