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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 Mg(2+) ions on their own and influx of divalent cations when expressed with the transient receptor potential ion chann...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348743/ https://www.ncbi.nlm.nih.gov/pubmed/37449820 http://dx.doi.org/10.7554/eLife.86129 |
Sumario: | Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg(2+) 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 Mg(2+) 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 Mg(2+) and Zn(2+) 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. |
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