Closed and open structures of the eukaryotic magnesium channel Mrs2 reveal the auto-ligand-gating regulation mechanism
The CorA/Mrs2 family of pentameric proteins are cardinal for the influx of Mg<sup>2+</sup> across cellular membranes, importing the cation to mitochondria in eukaryotes. Yet, the conducting and regulation mechanisms of permeation remain elusive, particularly for the eukaryotic Mrs2 members. Here, we report closed and open Mrs2 cryo-electron microscopy structures, accompanied by functional characterization. Mg<sup>2+</sup> flux is permitted by a narrow pore, gated by methionine and arginine residues in the closed state. Transition between the conformations is orchestrated by two pairs of conserved sensor-serving Mg<sup>2+</sup>-binding sites in the mitochondrial matrix lumen, located in between monomers. At lower levels of Mg<sup>2+</sup>, these ions are stripped, permitting an alternative, symmetrical shape, maintained by the RDLR motif that replaces one of the sensor site pairs in the open conformation. Thus, our findings collectively establish the molecular basis for selective Mg<sup>2+</sup> influx of Mrs2 and an auto-ligand-gating regulation mechanism.
Authors
- Gabriele Meloni (ORCID: https://orcid.org/0000-0003-4976-1401)
- Kefeng Lu (ORCID: https://orcid.org/0000-0001-8200-9380)
- Sara I. Liin (ORCID: https://orcid.org/0000-0001-8493-0114)
- Rhiza Lyne E. Villones (ORCID: https://orcid.org/0000-0002-0865-5189)
- Pontus Gourdon (ORCID: https://orcid.org/0000-0002-8631-3539)
- Karin Lindkvist‐Petersson (ORCID: https://orcid.org/0000-0002-5209-3160)
- Johan Wallerstein (ORCID: https://orcid.org/0009-0005-9832-5210)
- Ping Li (ORCID: https://orcid.org/0000-0002-7364-3301)
- Peng Huang (ORCID: https://orcid.org/0000-0001-8556-5606)
- Shiyan Liu (ORCID: https://orcid.org/0009-0009-6116-1506)
- Kristine Steen Jensen (ORCID: https://orcid.org/0000-0001-9174-8361)
Institutions
- Linköping University (SE)
- University of Copenhagen (DK)
- The University of Texas at Dallas (US)
- Lund University (SE)
- Sichuan University (CN)
- State Key Laboratory of Biotherapy
Publication Details
- Journal
- Nature Structural & Molecular Biology
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1038/s41594-024-01432-1
- Citations
- 6
- Primary Topic
- Magnesium in Health and Disease
- Type
- article
- Field-Weighted Citation Impact
- 1.86
Funders
- National Science Foundation
- Kempe Foundation
- Carl Tryggers Stiftelse för Vetenskaplig Forskning
- Lunds Universitet
- Lundbeckfonden
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Danmarks Frie Forskningsfond
- Umeå Universitet
- Kempestiftelserna
- Stockholms Universitet
- Science for Life Laboratory
- H. Lundbeck A/S
- National Institutes of Health
- National Institute of General Medical Sciences
- Division of Chemistry