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bioRxiv · 10.1101/2023.08.22.553867

Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms

Lai, L. T. F.·Balaraman, J.·Zhou, F.·Matthies, D.
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Abstract

Magnesium ions (Mg2+) play an essential role in cellular physiology. In mitochondria, protein and ATP synthesis and various metabolic pathways are directly regulated by Mg2+. MRS2, a magnesium channel located in the inner mitochondrial membrane, mediates the influx of Mg2+ into the mitochondrial matrix and regulates Mg2+ homeostasis. Knockdown of MRS2 in human cells leads to reduced uptake of Mg2+ into mitochondria and disruption of the mitochondrial metabolism. Despite the importance of MRS2, the Mg2+ translocation and regulation mechanisms of MRS2 are still unclear. Here, using cryo-EM we determined the structure of human MRS2 in the presence and absence of Mg2+ at 2.8 [A] and 3.3 [A], respectively. From the homo-pentameric structures, we identified R332 and M336 as major gating residues, which were then tested using mutagenesis and two cellular divalent ion uptake assays. A network of hydrogen bonds was found connecting the gating residue R332 to the soluble domain, potentially regulating the gate. Two Mg2+-binding sites were identified in the MRS2 soluble domain, distinct from the two sites previously reported in CorA, a homolog of MRS2 in prokaryotes. Altogether, this study provides the molecular basis for understanding the Mg2+ translocation and regulatory mechanisms of MRS2.

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Lai, L. T. F., Balaraman, J., Zhou, F., Matthies, D.. 2023-08-23. Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms. https://doi.org/10.1101/2023.08.22.553867

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