Copper (Cu) is an essential transition metal providing activity to key enzymes in the human body. To regulate the levels and avoid toxicity, cells have developed elaborate systems for loading these enzymes with Cu. Most Cu-dependent enzymes obtain the metal from the membrane-bound Cu pumps ATP7A/B in the Golgi network. ATP7A/B receives Cu from the cytoplasmic Cu chaperone Atox1 that acts as the cytoplasmic shuttle between the cell membrane Cu importer, Ctr1 and ATP7A/B. Biological, genetic and structural efforts have provided a tremendous amount of information for how the proteins in this pathway work. Nonetheless, basic mechanistic-biophysical questions (such as how and where ATP7A/B receives Cu, how ATP7A/B conformational changes and domain–domain interactions facilitate Cu movement through the membrane, and, finally, how target polypeptides are loaded with Cu in the Golgi) remain elusive. In this perspective, unresolved inquiries regarding ATP7A/B mechanism will be highlighted. The answers are important from a fundamental view, since mechanistic aspects may be common to other metal transport systems, and for medical purposes, since many diseases appear related to Cu transport dysregulation.

中文翻译：

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人类铜泵机制中未解决的问题

铜 (Cu) 是一种重要的过渡金属，可为人体关键酶提供活性。为了调节水平并避免毒性，细胞已经开发出复杂的系统来为这些酶加载铜。大多数铜依赖性酶从高尔基网络中的膜结合铜泵 ATP7A/B 中获取金属。ATP7A/B 接收来自细胞质 Cu 伴侣 Atox1 的 Cu，Atox1 充当细胞膜 Cu 输入蛋白 Ctr1 和 ATP7A/B 之间的细胞质穿梭。生物学、遗传和结构方面的努力为该途径中的蛋白质如何工作提供了大量信息。尽管如此，基本的机械-生物物理问题（例如 ATP7A/B 如何以及在何处接收 Cu，ATP7A/B 构象变化和域-域相互作用如何促进 Cu 通过膜移动，最后，靶多肽如何在高尔基体中加载铜）仍然难以捉摸。从这个角度来看，将突出显示有关 ATP7A/B 机制的未解决问题。从基本角度来看，答案很重要，因为机械方面可能与其他金属运输系统和医疗目的相同，因为许多疾病似乎与铜运输失调有关。