Structure of the Wilson disease copper transporter ATP7B Journal Article


Authors: Bitter, R. M.; Oh, S.; Deng, Z.; Rahman, S.; Hite, R. K.; Yuan, P.
Article Title: Structure of the Wilson disease copper transporter ATP7B
Abstract: 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. Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
Keywords: cell proliferation; electron microscopy; disease control; membrane transport; copper; wilson disease; neurodegenerative diseases; electron microscopes; cytoplasmic domains; atpases; rational functions; amino terminus; cellulars; copper homeostasis; copper transport; metal binding domain; p-type
Journal Title: Science Advances
Volume: 8
Issue: 9
ISSN: 2375-2548
Publisher: Amer Assoc Advancement Science  
Date Published: 2022-03-04
Start Page: eabl5508
Language: English
DOI: 10.1126/sciadv.abl5508
PUBMED: 35245129
PROVIDER: scopus
PMCID: PMC8896786
DOI/URL:
Notes: Article -- Export Date: 1 April 2022 -- Source: Scopus
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  1. Richard Kevin Hite
    25 Hite
  2. Secheol Oh
    6 Oh