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结构洞察 CNNM-TRPM7 二价阳离子摄取的调控通过小 GTPase ARL15。

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

机构信息

Department of Biochemistry, McGill University, Montreal, Canada.

Centre de recherche en biologie structurale, McGill University, Montréal, Canada.

出版信息

Elife. 2023 Jul 14;12:e86129. doi: 10.7554/eLife.86129.

DOI:10.7554/eLife.86129
PMID:37449820
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10348743/
Abstract

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 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 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 and Zn 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.

摘要

胱硫醚-β-合酶 (CBS)-对域二价金属阳离子转运介体 (CNNMs) 是一个进化上保守的镁转运体家族。它们可以在自身表达的情况下促进镁离子的外排，并且在与瞬时受体电位离子通道亚家族 M 成员 7 (TRPM7) 表达时促进二价阳离子的内流。最近，ADP-核糖基化因子样 GTP 酶 15 (ARL15) 已被确定为 CNNM 结合伴侣，并抑制 TRPM7 介导的二价阳离子内流。在这里，我们将 ARL15 表征为 GTP 和 CNNM 结合蛋白，并证明 ARL15 还抑制 CNNM2 的镁外排。ARL15 与 CNNM2 CBS 对域的复合物晶体结构揭示了结合的分子基础，并确定了特异性阻断结合的突变。结合缺陷的 ARL15 突变体 R95A 无法抑制 CNNM 和 TRPM7 转运镁和锌离子。结构分析和与再生肝磷酸酶 2 (PRL2 或 PTP4A2) 的结合实验表明，ARL15 和 PRLs 竞争与 CNNM 的结合，以协调 CNNM 和 TRPM7 介导的离子转运的调节。

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