人源威尔逊病铜转运蛋白 ATP7B 的结构。
Structures of the human Wilson disease copper transporter ATP7B.
机构信息
Department of Medical Genetics and Center for Rare Diseases, and Department of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
Department of Biophysics, and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
出版信息
Cell Rep. 2023 May 30;42(5):112417. doi: 10.1016/j.celrep.2023.112417. Epub 2023 Apr 18.
The P-type ATPase ATP7B exports cytosolic copper and plays an essential role in the regulation of cellular copper homeostasis. Mutants of ATP7B cause Wilson disease (WD), an autosomal recessive disorder of copper metabolism. Here, we present cryoelectron microscopy (cryo-EM) structures of human ATP7B in the E1 state in the apo, the putative copper-bound, and the putative cisplatin-bound forms. In ATP7B, the N-terminal sixth metal-binding domain (MBD6) binds at the cytosolic copper entry site of the transmembrane domain (TMD), facilitating the delivery of copper from the MBD6 to the TMD. The sulfur-containing residues in the TMD of ATP7B mark the copper transport pathway. By comparing structures of the E1 state human ATP7B and E2-P state frog ATP7B, we propose the ATP-driving copper transport model of ATP7B. These structures not only advance our understanding of the mechanisms of ATP7B-mediated copper export but can also guide the development of therapeutics for the treatment of WD.
P 型 ATP 酶 ATP7B 将细胞质中的铜输出，并在调节细胞内铜稳态方面发挥着重要作用。ATP7B 的突变会导致威尔逊病（WD），这是一种常染色体隐性遗传的铜代谢紊乱疾病。在这里，我们呈现了人类 ATP7B 在 E1 状态下的无铜结合、假定铜结合和假定顺铂结合形式的 cryo-EM 结构。在 ATP7B 中，N 端第六个金属结合域（MBD6）结合在跨膜域（TMD）的细胞质铜进入位点，促进铜从 MBD6 到 TMD 的传递。ATP7B 的 TMD 中的含硫残基标记了铜转运途径。通过比较 E1 状态下人类 ATP7B 和 E2-P 状态下青蛙 ATP7B 的结构，我们提出了 ATP7B 介导的铜转运模型。这些结构不仅推进了我们对 ATP7B 介导的铜输出机制的理解，还可以指导治疗 WD 的治疗方法的开发。
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