ATP-dependent modulation of MgtE in Mg²⁺ homeostasis

Magnesium is an essential ion for numerous physiological processes. MgtE is a Mg²⁺ selective channel involved in the maintenance of intracellular Mg²⁺ homeostasis, whose gating is regulated by intracellular Mg²⁺ levels. Here, we report that ATP binds to MgtE, regulating its Mg²⁺-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 Mg²⁺ within physiological concentrations of this divalent cation, enabling MgtE to function as an in vivo Mg²⁺ sensor. ATP dissociation from MgtE upregulates Mg²⁺ influx at both high and low intracellular Mg²⁺ 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 Mg²⁺ homeostasis.MgtE is an Mg²⁺ transporter involved in Mg²⁺ homeostasis. Here, the authors report that ATP regulates the Mg⁺²-dependent gating of MgtE and use X-ray crystallography combined with functional studies to propose the molecular mechanisms involved in this process.