Crystal structure of an archaeal CorB magnesium transporter

Abstract

CNNM/CorB proteins are a broadly conserved family of integral membrane proteins with close to 90,000 protein sequences known. They are associated with Mg2+ transport but it is not known if they mediate transport themselves or regulate other transporters. Here, we determine 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 π-helix. In the absence of Mg2+-ATP, the CBS-pair domain adopts an elongated dimeric configuration with previously unobserved domain-domain contacts. Hydrogen-deuterium exchange mass spectrometry, analytical ultracentrifugation, and molecular dynamics experiments support a role of the structural rearrangements in mediating Mg2+-ATP sensing. Lastly, we use an in vitro, liposome-based assay to demonstrate direct Mg2+ transport by CorB proteins. These structural and functional insights provide a framework for understanding function of CNNMs in Mg2+ transport and associated diseases.

CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells

“…The fact that the CNNM4-S196P mutant disrupted the Mg 2+ -lowering activity of CNNM4 without affecting CNNM-stimulated divalent cation influx, however, adds further evidence that CNNMs Mg efflux activity is independent of its divalent cation influx activity. Thus, CNNM-stimulated influx of divalent cations occurs through TRPM7, while efflux of Mg 2+ is believed to be achieved by direct binding of Mg 2+ to CNNMs, which is supported by recent structural studies of the related CorB and CorC proteins [29,56].…”

“…CNNMs are transmembrane membrane proteins that contain a Bateman module composed of 2 cystathionine beta-synthase (CBS) motifs [26][27][28]. The Bateman module of CNNMs bind to Mg 2+ -ATP [28], which has been demonstrated to cause significant structural changes in the Bateman module [26], affecting the orientation of the domain with the CNNM transmembrane region [29]. CNNMs have also been found to be regulated by members of the phosphatases of regenerating liver (PRLs) family, which also bind to the Bateman module [30][31][32].…”

The double lives of phosphatases of regenerating liver: A structural view of their catalytic and noncatalytic activities

“…A , model of PRL bound to a Mg 2+ transporter CNNM protein. The model is based on structures of bacterial and human CNNM proteins and their complexes with PRLs ( 44 , 47 , 62 , 63 , 93 , 94 , 95 , 96 , 97 ). B , the PRL catalytic site controls the affinity of CNNM binding.…”

Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure

“…Gene mutations related to the regulation of Mg 2+ transport in the DCT can cause renal hypomagnesemia. These genes include SLC12A3 encoding thiazide-sensitive NCC, TRMP6 encoding apical TRPM6 channel, HNF1B encoding HNF1β, PCBD1 encoding PCBD1, EGF encoding EGF, EGFR encoding EGFR, KCNJ10 encoding Kir4.1 (EAST syndrome), KCNA1 encoding Kv1.1, FXYD2 encoding γ-subunit of Na + -K + ATPase, and CNNM2 encoding CNNM2 (cyclin M2) ( Meij et al, 2003 ; Groenestege et al, 2007 ; Adalat et al, 2009 ; Glaudemans et al, 2009 ; Reichold et al, 2010 ; de Baaij et al, 2012 ; Ferrè et al, 2014 ; Sponder et al, 2016 ; Chen et al, 2021 ).…”

“…In 2011 and 2014, mutations in CNNM2 predominantly expressed in the DCT and brain were first reported to cause autosomal-dominant (majority) or recessive (minority) renal hypomagnesemia with seizure and intellectual disability (HSMR) ( de Baaij et al, 2012 ; Chen et al, 2021 ; Franken et al, 2021 ; Accogli et al, 2019 ; Arjona and de Baaij, 2018 ; Bamhraz et al, 2021 ). In humans, the cyclin M (CNNM, also formerly known as ancient conserved domain protein, ACDP) family has four member proteins (CNNM1–4) sharing evolutionary homology.…”