1. Department of Biological Information, Graduate School of Bioscience and Biotechnology,
2. Center for Biological Resources and Informatics, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa 226-8501, Japan
3. SORST, JST, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan

Correspondence to: Osamu Nureki^1,3 Correspondence and requests for materials should be addressed to O.N. (Email: nureki@bio.titech.ac.jp).

Abstract

The magnesium ion Mg²⁺ is a vital element involved in numerous physiological processes. Mg²⁺ has the largest hydrated radius among all cations, whereas its ionic radius is the smallest. It remains obscure how Mg²⁺ transporters selectively recognize and dehydrate the large, fully hydrated Mg²⁺ cation for transport¹. Recently the crystal structures of the CorA Mg²⁺ transporter^{2, 3, 4, 5} were reported^{6, 7, 8}. The MgtE family of Mg²⁺ transporters is ubiquitously distributed in all phylogenetic domains^{9, 10, 11}, and human homologues have been functionally characterized and suggested to be involved in magnesium homeostasis^{12, 13, 14}. However, the MgtE transporters have not been thoroughly characterized. Here we determine the crystal structures of the full-length Thermus thermophilus MgtE at 3.5 Å resolution, and of the cytosolic domain in the presence and absence of Mg²⁺ at 2.3 Å and 3.9 Å resolutions, respectively. The transporter adopts a homodimeric architecture, consisting of the carboxy-terminal five transmembrane domains and the amino-terminal cytosolic domains, which are composed of the superhelical N domain and tandemly repeated cystathionine--synthase domains. A solvent-accessible pore nearly traverses the transmembrane domains, with one potential Mg²⁺ bound to the conserved Asp 432 within the pore. The transmembrane (TM)5 helices from both subunits close the pore through interactions with the 'connecting helices', which connect the cystathionine--synthase and transmembrane domains. Four putative Mg²⁺ ions are bound at the interface between the connecting helices and the other domains, and this may lock the closed conformation of the pore. A structural comparison of the two states of the cytosolic domains showed the Mg²⁺-dependent movement of the connecting helices, which might reorganize the transmembrane helices to open the pore. These findings suggest a homeostasis mechanism, in which Mg²⁺ bound between cytosolic domains regulates Mg²⁺ flux by sensing the intracellular Mg²⁺ concentration. Whether this presumed regulation controls gating of an ion channel or opening of a secondary active transporter remains to be determined.

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