Bitter Ryan M, Oh SeCheol, Deng Zengqin, Rahman Suhaila, Hite Richard K, Yuan Peng
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sci Adv. 2022 Mar 4;8(9):eabl5508. doi: 10.1126/sciadv.abl5508.
ATP7A and ATP7B, two homologous copper-transporting P1B-type ATPases, play crucial roles in cellular copper homeostasis, and mutations cause Menkes and Wilson diseases, respectively. ATP7A/B contains a P-type ATPase core consisting of a membrane transport domain and three cytoplasmic domains, the A, P, and N domains, and a unique amino terminus comprising six consecutive metal-binding domains. Here, we present a cryo-electron microscopy structure of frog ATP7B in a copper-free state. Interacting with both the A and P domains, the metal-binding domains are poised to exert copper-dependent regulation of ATP hydrolysis coupled to transmembrane copper transport. A ring of negatively charged residues lines the cytoplasmic copper entrance that is presumably gated by a conserved basic residue sitting at the center. Within the membrane, a network of copper-coordinating ligands delineates a stepwise copper transport pathway. This work provides the first glimpse into the structure and function of ATP7 proteins and facilitates understanding of disease mechanisms and development of rational therapies.
ATP7A和ATP7B是两种同源的铜转运P1B型ATP酶，在细胞铜稳态中起关键作用，其突变分别导致门克斯病和威尔逊病。ATP7A/B包含一个P型ATP酶核心，由一个膜转运结构域和三个细胞质结构域（A、P和N结构域）以及一个独特的氨基末端组成，该氨基末端包含六个连续的金属结合结构域。在此，我们展示了处于无铜状态的青蛙ATP7B的冷冻电子显微镜结构。金属结合结构域与A和P结构域相互作用，准备对与跨膜铜转运偶联的ATP水解进行铜依赖性调节。一圈带负电荷的残基排列在细胞质铜入口处，该入口可能由位于中心的保守碱性残基控制。在膜内，铜配位配体网络描绘了一条逐步的铜转运途径。这项工作首次揭示了ATP7蛋白的结构和功能，有助于理解疾病机制并开发合理的治疗方法。
