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Structural mechanism of TRPM7 channel regulation by intracellular magnesium.

Eva SchmidtChamali NarangodaWolfgang NörenbergMiyuki EgawaAnna RössigMarion LeonhardtMichael SchaeferSusanna ZierlerMaria G KurnikovaThomas GudermannVladimir Chubanov
Published in: Cellular and molecular life sciences : CMLS (2022)
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.
Keyphrases
  • molecular dynamics
  • transcription factor
  • density functional theory
  • stem cells
  • heavy metals
  • genome wide
  • risk assessment
  • reactive oxygen species
  • bone marrow
  • dna methylation