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Structure of the Wilson disease copper transporter ATP7B
- Source :
- Science Advances. 8
- Publication Year :
- 2022
- Publisher :
- American Association for the Advancement of Science (AAAS), 2022.
-
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.
- Subjects :
- Multidisciplinary
Subjects
Details
- ISSN :
- 23752548
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Science Advances
- Accession number :
- edsair.doi.dedup.....7b91f48e90eca9d18efe4be554950f9b
- Full Text :
- https://doi.org/10.1126/sciadv.abl5508