Structural insights into regulation of CNNM-TRPM7 divalent cation uptake by the small GTPase ARL15.

Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg2+ ions on their own and influx of divalent cations when expressed with the transient receptor potential ion channel subfamily M member 7 (TRPM7). Recently, ADP-ribosylation factor-like GTPase 15 (ARL15) has been identified as CNNM-binding partner and an inhibitor of divalent cation influx by TRPM7. Here, we characterize ARL15 as a GTP and CNNM-binding protein and demonstrate that ARL15 also inhibits CNNM2 Mg2+ efflux. The crystal structure of a complex between ARL15 and CNNM2 CBS-pair domain reveals the molecular basis for binding and allowed the identification of mutations that specifically block binding. A binding deficient ARL15 mutant, R95A, failed to inhibit CNNM and TRPM7 transport of Mg2+ and Zn2+ ions. Structural analysis and binding experiments with phosphatase of regenerating liver 2 (PRL2 or PTP4A2) showed that ARL15 and PRLs compete for binding CNNM to coordinate regulation of ion transport by CNNM and TRPM7. © 2023, Mahbub, Kozlov et al.

Citation

Luba Mahbub, Guennadi Kozlov, Pengyu Zong, Emma L Lee, Sandra Tetteh, Thushara Nethramangalath, Caroline Knorn, Jianning Jiang, Ashkan Shahsavan, Lixia Yue, Loren Runnels, Kalle Gehring. Structural insights into regulation of CNNM-TRPM7 divalent cation uptake by the small GTPase ARL15. eLife. 2023 Jul 14;12

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PMID: 37449820

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