A repulsion mechanism explains magnesium permeation and selectivity in CorA

Abstract

Magnesium (Mg 2+) plays a central role in biology, regulating the activity of many enzymes and stabilizing the structure of key macromolecules. In bacteria, CorA is the primary source of Mg 2+ uptake and is self-regulated by intracellular Mg 2+. Using a gating mutant at the divalent ion binding site, we were able to characterize CorA selectivity and permeation properties to both mono- ). Selectivity against monovalent cations takes place via Mg 2+ binding at a high-affinity site, formed by the Gly-Met-Asn signature sequence (Gly312 and Asn314) at the extracellular side of the pore. This mechanism is reminiscent of repulsion models proposed for Ca 2+ channel selectivity despite differences in sequence and overall structure.ion channels | electrophysiology | Mg 2+ selectivity | AMFE

Cryo-EM Structures of the Magnesium Channel CorA Reveal Symmetry Break upon Gating

“…Furthermore, we were able to detect density for coordinated Mg 2+ at the subunit interfaces (Fig. 2B), as well as strong peaks for putative Mg 2+ along the permeation path near the GMN selectivity filter [Asn314 at the periplasmic loop (Dalmas et al, 2014a; Palombo et al, 2013; Payandeh and Pai, 2006)], and at the other end of the pathway near Asp277 (Fig. 2C).…”

“…Recent experimental evidence suggests that Mg 2+ homeostasis through CorA takes place via a negative feedback loop, where Mg 2+ binding at the inter-subunit interfaces leads to channel closure, whereas low Mg 2+ concentrations tend to promote the transition to the open, conductive state (Dalmas et al, 2014b; Pfoh et al, 2012). Therefore, in CorA, Mg 2+ acts as both the gating ligand and the selected charge carrier against other extracellular cations (Dalmas et al, 2014a). …”

“…In most ligand-gated ion channels, ligand binding provides the energy required for a series of structural rearrangements that lead to the formation of a water-filled permeation pathway. In contrast, Mg 2+ -bound CorA forms a stable five-fold symmetric closed conformation, where five equivalent subunits associate to generate a long (~50 Å), narrow, presumably non-conductive pathway along the channel central axis (Dalmas et al, 2014a; Neale et al, 2015; Svidova et al, 2011). This finding suggests that the energetics and mechanism of CorA activation/deactivation differ from those of other ligand-gated channels.…”

Critical Issues in the Study of Magnesium Transport Systems and Magnesium Deficiency Symptoms in Plants

“…In this context, CorA-type transporters are referred as the 2-TM-GxN type [ 46 ]. Indeed, the essential role of the GMN tripeptide in ion selectivity was clearly demonstrated by mutagenesis studies showing that single amino acid substitutions in this motif are sufficient to abolish Mg 2+ transport activity [ 47 , 48 , 49 , 50 ]. Recent developments in crystal structure analysis have further provided a unique gating model for the Mg 2+ transport system through CorA, in which the GMN motif played a critical role for ion selectivity [ 33 , 50 , 51 ].…”

“…Recent developments in crystal structure analysis have further provided a unique gating model for the Mg 2+ transport system through CorA, in which the GMN motif played a critical role for ion selectivity [ 33 , 50 , 51 ]. If Mg 2+ is absent from the test solution, CorA can import various divalent cations including Ca 2+ and Mn 2+ , acting as a nonselective cation channel [ 49 ]. Meanwhile, only a small amount of Mg 2+ introduced to the test solution could block the Ca 2+ currents with a high affinity ( K D = 1.6 μM) [ 49 ], making CorA a Mg 2+ -selective channel in a physiological condition.…”