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.