Structural mechanism of TRPM7 channel regulation by intracellular magnesium
Eva Schmidt, Chamali Narangoda, Wolfgang Nörenberg, Miyuki Egawa, Anna Rössig, Marion Leonhardt, Michael Schaefer, Susanna Zierler, Maria G. Kurnikova, Thomas Gudermann, Vladimir Chubanov
Abstract
Abstract Zn 2+ , Mg 2+ and Ca 2+ are essential divalent cations implicated in many metabolic processes and signalling pathways. An emerging new paradigm is that the organismal balance of these cations predominantly depends on a common gatekeeper, the channel-kinase TRPM7. Despite extensive electrophysiological studies and recent cryo-EM analysis, an open question is how the channel activity of TRPM7 is activated. Here, we performed site-directed mutagenesis of mouse TRPM7 in conjunction with patch-clamp assessment of whole-cell and single-channel activity and molecular dynamics (MD) simulations to show that the side chains of conserved N1097 form an inter-subunit Mg 2+ regulatory site located in the lower channel gate of TRPM7. Our results suggest that intracellular Mg 2+ binds to this site and stabilizes the TRPM7 channel in the closed state, whereas the removal of Mg 2+ favours the opening of TRPM7. Hence, our study identifies the structural underpinnings through which the TRPM7 channel is controlled by cytosolic Mg 2+ , representing a new structure–function relationship not yet explored among TRPM channels.