Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms
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 mitochon...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42599-3 |
| _version_ | 1797630089966387200 |
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| author | Louis Tung Faat Lai Jayashree Balaraman Fei Zhou Doreen Matthies |
| author_facet | Louis Tung Faat Lai Jayashree Balaraman Fei Zhou Doreen Matthies |
| author_sort | Louis Tung Faat Lai |
| collection | DOAJ |
| description | 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 report the structures of human MRS2 in the presence and absence of Mg2+ at 2.8 Å and 3.3 Å, respectively. From the homo-pentameric structures, we identify R332 and M336 as major gating residues, which are then tested using mutagenesis and two cellular divalent ion uptake assays. A network of hydrogen bonds is found connecting the gating residue R332 to the soluble domain, potentially regulating the gate. Two Mg2+-binding sites are 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. |
| first_indexed | 2024-03-11T11:03:04Z |
| format | Article |
| id | doaj.art-3b41cf47264840568180b1b5c7176372 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-11T11:03:04Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-3b41cf47264840568180b1b5c71763722023-11-12T12:21:50ZengNature PortfolioNature Communications2041-17232023-11-0114111010.1038/s41467-023-42599-3Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanismsLouis Tung Faat Lai0Jayashree Balaraman1Fei Zhou2Doreen Matthies3Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthUnit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthUnit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthUnit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthAbstract 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 report the structures of human MRS2 in the presence and absence of Mg2+ at 2.8 Å and 3.3 Å, respectively. From the homo-pentameric structures, we identify R332 and M336 as major gating residues, which are then tested using mutagenesis and two cellular divalent ion uptake assays. A network of hydrogen bonds is found connecting the gating residue R332 to the soluble domain, potentially regulating the gate. Two Mg2+-binding sites are 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.https://doi.org/10.1038/s41467-023-42599-3 |
| spellingShingle | Louis Tung Faat Lai Jayashree Balaraman Fei Zhou Doreen Matthies Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms Nature Communications |
| title | Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms |
| title_full | Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms |
| title_fullStr | Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms |
| title_full_unstemmed | Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms |
| title_short | Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms |
| title_sort | cryo em structures of human magnesium channel mrs2 reveal gating and regulatory mechanisms |
| url | https://doi.org/10.1038/s41467-023-42599-3 |
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