Structural mechanism of TRPM7 channel regulation by intracellular magnesium

Schmidt, Eva; Narangoda, Chamali; Nörenberg, Wolfgang; Egawa, Miyuki; Rössig, Anna; Leonhardt, Marion; Schäfer, Michael; Zierler, Susanna; Kurnikova, Maria G.; Gudermann, Thomas und Chubanov, Vladimir (2022): Structural mechanism of TRPM7 channel regulation by intracellular magnesium. In: Cellular and Molecular Life Sciences, Bd. 79, Nr. 5

Abstract

Zn2+, Mg2+ and Ca2+ 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 Mg2+ regulatory site located in the lower channel gate of TRPM7. Our results suggest that intracellular Mg2+ binds to this site and stabilizes the TRPM7 channel in the closed state, whereas the removal of Mg2+ favours the opening of TRPM7. Hence, our study identifies the structural underpinnings through which the TRPM7 channel is controlled by cytosolic Mg2+, representing a new structure-function relationship not yet explored among TRPM channels.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1420-682X
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892