Crystal structure of a bacterial CNNM magnesium transporter

Abstract

CBS-pair domain divalent metal cation transport mediators (CNNMs) are a broadly conserved family of integral membrane proteins with close to 90,000 protein sequences known. CNNM proteins are associated with Mg2+ transport but it is not known if they mediate transport themselves or regulate other transporters. Here, we determined the crystal structure of an archaeal CNNM protein with Mg2+-ATP bound. The structure reveals a novel transmembrane fold for the DUF21 domain, the largest family of domains of unknown function. The protein has a negatively charged cavity that penetrates halfway through the membrane suggesting it functions as a cation transporter. The cytosolic portion of the protein is comprised of highly charged four-helix bundle and a CBS-pair domain. HDX-MS experiments, molecular dynamics, and additional crystal structures show that the cytosolic domains undergo large conformational changes upon nucleotide binding suggesting a mechanism of regulation shared between human and bacterial orthologs. The molecular characterization of CNNM proteins has profound implications for understanding their biological functions in human diseases, including cancer, and in animals, bacteria and plants.

Identification and mechanistic analysis of an inhibitor of the CorC Mg2+ transporter

“…The recently determined structures of the TM and CBS domains of the CorC Na + /Mg 2+ antiporter from Thermus parvatiensis (TpCorC) revealed the mechanisms of Mg 2+ and ATP binding, respectively . Subsequently, the crystal structures of CorC from Methanoculleus thermophiles, containing the TM and CBS domains, were also reported on bioRxiv (Chen et al, 2021). Furthermore, multiple structures containing the CBS domain of CNNM proteins have also been reported thus far (Chen et al, 2018(Chen et al, , 2020Corral-Rodriguez et al, 2014;Gimenez-Mascarell et al, 2019;Gimé nez-Mascarell et al, 2017Gulerez et al, 2016;Zhang et al, 2017).…”