Transition metals, such as zinc, are essential micronutrients in all organisms, but also highly toxic in excessive amounts. Heavy-metal transporting P-type (P_IB) ATPases are crucial for homeostasis, conferring cellular detoxification and redistribution through transport of these ions across cellular membranes. No structural information is available for the P_IB-4-ATPases, the subclass with the broadest cargo scope, and hence even their topology remains elusive. Here we present structures and complementary functional analyses of an archetypal P_IB-4-ATPases, sCoaT from Sulfitobacter sp. NAS14-1. The data disclose the architecture, devoid of classical so-called heavy metal binding domains, and provides fundamentally new insights into the mechanism and diversity of heavy-metal transporters. We reveal several novel P-type ATPase features, including a dual role in heavy-metal release, and as an internal counter ion, of an invariant, central histidine. We also establish that the turn-over of P_IB-ATPases is potassium independent, contrasting to many other P-type ATPases. Combined with new inhibitory compounds, our results open up for efforts in e.g. drug discovery, since P_IB-4-ATPases function as virulence factors in many pathogens.

中文翻译：

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PIB-4型ATP酶的结构和离子释放机制

过渡金属，例如锌，是所有生物体中必不可少的微量营养素，但过量使用也会产生剧毒。重金属运输 P 型 ( _PIB ) ATP 酶对于体内平衡至关重要，通过这些离子跨细胞膜的运输赋予细胞解毒和重新分配。P _IB-4 -ATPases没有结构信息，这是具有最广泛货物范围的子类，因此即使它们的拓扑结构也难以捉摸。在这里，我们展示了原型 P _{IB-4 的}结构和互补功能分析-ATPases，来自 Sulfitobacter sp. 的 sCoaT。NAS14-1。该数据揭示了没有经典的所谓重金属结合域的结构，并为重金属转运蛋白的机制和多样性提供了全新的见解。我们揭示了几个新的 P 型 ATPase 特征，包括在重金属释放中的双重作用，以及作为内部抗衡离子，不变的中枢组氨酸。我们还确定 P _IB -ATPases 的周转不依赖钾，这与许多其他 P 型 ATPases 形成对比。结合新的抑制性化合物，我们的结果为例如药物发现方面的努力开辟了道路，因为 P _IB-4 -ATP 酶在许多病原体中起毒力因子的作用。