ATP-dependent modulation of MgtE in Mg 2+ homeostasis

Magnesium is an essential ion for numerous physiological processes. MgtE is a Mg 2+ selective channel involved in the maintenance of intracellular Mg 2+ homeostasis, whose gating is regulated by intracellular Mg 2+ levels. Here, we report that ATP binds to MgtE, regulating its Mg 2+ -dependent gating. Crystal structures of MgtE–ATP complex show that ATP binds to the intracellular CBS domain of MgtE. Functional studies support that ATP binding to MgtE enhances the intracellular domain affinity for Mg 2+ within physiological concentrations of this divalent cation, enabling MgtE to function as an in vivo Mg 2+ sensor. ATP dissociation from MgtE upregulates Mg 2+ influx at both high and low intracellular Mg 2+ concentrations. Using site-directed mutagenesis and structure based-electrophysiological and biochemical analyses, we identify key residues and main structural changes involved in the process. This work provides the molecular basis of ATP-dependent modulation of MgtE in Mg 2+ homeostasis.