Evolutionary analysis of Slc11 mechanism of proton-coupled metal-ion transmembrane import

Abstract

Determination of the crystal structure of ScaDMT, a member of the Slc11 family, provided opportunity to advance understanding of proton-dependent metal-ion uptake by interfacing Slc11 molecular evolution and structural biology. Slc11 carriers belong to the ancient and broadly distributed APC superfamily characterized by the pseudo-symmetric LeuT-fold. This fold comprises two topologically inverted repeats (protomers) that exchange alternate configurations during carrier cycling. Examining ScaDMT molecule inserted within a model membrane allowed to pinpoint residues that may interact with surrounding lipid solvent molecules. Three-dimensional mapping of Slc11-specific sites demonstrated they distribute at the protomer interface, along the transmembrane ion-conduction pathway. Functional sites were predicted by modeling hypothetical ScaDMT alternate conformers based on APC templates; these candidate homologous sites were found to co-localize with Slc11-specific sites, a distribution pattern that fits the functional diversity in the APC superfamily. Sites that diverged among eukaryotic Slc11 (Nramp) types were located in transmembrane helices that may participate in discrete steps during co-substrate translocation, suggesting these sites influence transport activity. Adding some functional dimension to Slc11 carrier evolution will inform molecular understanding of metal-ion transport selectivity and regulation, Slc11 physiological roles and contribution to host resistance to microbial infection.

Keywords

• metal-ion
• membrane transport
• proton-coupling
• solute carrier family 11
• proton-dependent Mn transporter
• natural resistance-associated macrophage protein
• divalent metal transporter
• LeuT fold
• amino acid-polyamine-organo-cation superfamily.