1.A.112.2.13
CorB (CNNM) has been structurally ellicidated.  Chen et al. 2021 determined the crystal structure of an archaeal CorB protein in two conformations (apo and Mg²⁺-ATP bound). The transmembrane DUF21 domain exists in an inward-facing conformation with a Mg²⁺ ion coordinated by a conserved pi-helix. In the absence of Mg²⁺-ATP, the CBS-pair domain adopts an elongated dimeric configuration with previously unobserved domain-domain contacts. A role of the structural rearrangements in mediating Mg²⁺-ATP sensing was suggested. An in vitro, liposome-based assay was used to demonstrate direct Mg²⁺ transport by CorB proteins (Chen et al. 2021).  CNNM2 and CNNM4 are found abundantly in the basolateral membrane of kidney and colon epithelial cells, where renal/intestinal (re)absorption of Mg²⁺ occurs. In humans, mutations in CNNM proteins are linked to two genetic diseases: CNNM2 mutations cause hypomagnesemia while mutations in CNNM4 are associated with Jalili syndrome. CNNM2-knockout mice are embryonic lethal, while loss of CNNM4 leads to male infertility and susceptibility to cancer. CNNMs are additionally implicated in hypertension, non-alcoholic steatohepatitis, and schizophrenia (Chen et al. 2021). CorB was proposed to mediate Mg²⁺ efflux together with CorC and CorD, in which CorC is a soluble protein that shares high sequence similarity to the cytosolic domains of CorB. Subsequently, many other CorB orthologs have been implicated in Mg²⁺ transport. For example, the Staphylococcus aureus ortholog, MpfA, is thought to function as a Mg²⁺ exporter as deletion mutants are unable to grow in the presence of high concentrations of magnesium. Disruption of the homologous gene (yhdP) in Bacillus subtilis leads to increased cellular Mg²⁺ content, again supporting a role in Mg²⁺ efflux (Chen et al. 2021).  MtCorB from a thermophilic archaeon (Methanoculleus thermophilus) has been crystalized and structurally illucidated (Chen et al. 2021).