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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