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The family of cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) is composed of four integral membrane proteins associated with Mg2+ transport. Structurally, CNNMs contain large cytosolic regions composed of a CBS-pair and a cyclic nucleotide-binding homology (CNBH) domain. How these regulate Mg2+ transport activity is unknown. Here, we determined the crystal structures of cytosolic fragments in two conformations: Mg2+-ATP-analog bound and ligand free. The structures reveal open and closed conformations with functionally important contacts not observed in structures of the individual domains. We also identified a second Mg2+-binding region in the CBS-pair domain and a different dimerization interface for the CNBH domain. Analytical ultracentrifugation and isothermal titration calorimetry experiments revealed a tight correlation between Mg2+-ATP binding and protein dimerization. Mutations that blocked either function prevented cellular Mg2+ efflux activity. The results suggest Mg2+ efflux is regulated by conformational changes associated with Mg2+-ATP binding to CNNM CBS-pair domains. Copyright © 2019 Elsevier Ltd. All rights reserved.


Yu Seby Chen, Guennadi Kozlov, Rayan Fakih, Meng Yang, Zhidian Zhang, Evgenii L Kovrigin, Kalle Gehring. Mg2+-ATP Sensing in CNNM, a Putative Magnesium Transporter. Structure (London, England : 1993). 2020 Mar 03;28(3):324-335.e4

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PMID: 31864811

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