Structural and functional comparison of magnesium transporters throughout evolution

Magnesium (Mg²⁺) is the most prevalent divalent intracellular cation. As co-factor in many enzymatic reactions, Mg²⁺ is essential for protein synthesis, energy production, and DNA stability. Disturbances in intracellular Mg²⁺ concentrations, therefore, unequivocally result in delayed cell growth and metabolic defects. To maintain physiological Mg²⁺ levels, all organisms rely on balanced Mg²⁺ influx and efflux via Mg²⁺ channels and transporters. This review compares the structure and the function of prokaryotic Mg²⁺ transporters and their eukaryotic counterparts. In prokaryotes, cellular Mg²⁺ homeostasis is orchestrated via the CorA, MgtA/B, MgtE, and CorB/C Mg²⁺ transporters. For CorA, MgtE, and CorB/C, the motifs that form the selectivity pore are conserved during evolution. These findings suggest that CNNM proteins, the vertebrate orthologues of CorB/C, also have Mg²⁺ transport capacity. Whereas CorA and CorB/C proteins share the gross quaternary structure and functional properties with their respective orthologues, the MgtE channel only shares the selectivity pore with SLC41 Na⁺/Mg²⁺ transporters. In eukaryotes, TRPM6 and TRPM7 Mg²⁺ channels provide an additional Mg²⁺ transport mechanism, consisting of a fusion of channel with a kinase. The unique features these TRP channels allow the integration of hormonal, cellular, and transcriptional regulatory pathways that determine their Mg²⁺ transport capacity. Our review demonstrates that understanding the structure and function of prokaryotic magnesiotropic proteins aids in our basic understanding of Mg²⁺ transport.