The CNNM/CorC family proteins are Mg²⁺ transporters that are widely distributed in all domains of life. In bacteria, CorC has been implicated in the survival of pathogenic microorganisms in their host environment and in resistance to antibiotic exposure. In humans, CNNM proteins are involved in a number of biological events, such as body absorption/reabsorption of Mg²⁺, hypertension, genetic disorders and tumour progression. Accordingly, both CorC and CNNM have attracted interest as therapeutic targets.
Despite the physiological importance of the CNNM/CorC family proteins, their Mg²⁺ transport mechanism is unclear, mainly due to the lack of a CNNM/CorC family protein structure that includes its transmembrane (TM) domain.
In this talk, we present the crystal structure of the CorC TM domain dimer in the presence of Mg²⁺. The CorC TM domain dimer consists of six TM helices surrounded by long, curved, amphipathic helices parallel to the membrane. Each protomer possesses a single Mg²⁺ binding site with a fully dehydrated Mg²⁺ ion coordinated to five amino acids, which highly contrasts with that of the known Mg²⁺ channel structures, where Mg²⁺ ions are typically fully-hydrated. The residues at the Mg²⁺ binding site are strictly conserved in both human CNNM2 and CNNM4, and many of these residues are associated with genetic diseases in humans.