Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases
(2024) In Nature Communications 15(1).- Abstract
Copper transporting P-type (P1B-1-) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P1B-1-ATPases remains poorly understood. In particular, the role of the intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations of a P1B-1-ATPase are combined to reveal that in many eukaryotes the MBD immediately prior to the ATPase core, MBD−1, serves a structural role, remodeling the ion-uptake region. In contrast, the MBD prior to MBD−1, MBD−2, likely assists in copper delivery to the ATPase core. Invariant Tyr, Asn and Ser residues in the transmembrane domain assist in... (More)
Copper transporting P-type (P1B-1-) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P1B-1-ATPases remains poorly understood. In particular, the role of the intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations of a P1B-1-ATPase are combined to reveal that in many eukaryotes the MBD immediately prior to the ATPase core, MBD−1, serves a structural role, remodeling the ion-uptake region. In contrast, the MBD prior to MBD−1, MBD−2, likely assists in copper delivery to the ATPase core. Invariant Tyr, Asn and Ser residues in the transmembrane domain assist in positioning sulfur-providing copper-binding amino acids, allowing for copper uptake, binding and release. As such, our findings unify previously conflicting data on the transport and regulation of P1B-1-ATPases. The results are critical for a fundamental understanding of cellular copper homeostasis and for comprehension of the molecular bases of P1B-1-disorders and ongoing clinical trials.
(Less)
- author
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 15
- issue
- 1
- article number
- 2690
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:38538615
- scopus:85188924528
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-024-47001-4
- language
- English
- LU publication?
- yes
- id
- 1537d66f-e122-4700-93cb-e88fab2a9b06
- date added to LUP
- 2024-04-16 10:20:24
- date last changed
- 2024-09-04 00:14:50
@article{1537d66f-e122-4700-93cb-e88fab2a9b06, abstract = {{<p>Copper transporting P-type (P<sub>1B-1</sub>-) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P<sub>1B-1</sub>-ATPases remains poorly understood. In particular, the role of the intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations of a P<sub>1B-1</sub>-ATPase are combined to reveal that in many eukaryotes the MBD immediately prior to the ATPase core, MBD<sup>−1</sup>, serves a structural role, remodeling the ion-uptake region. In contrast, the MBD prior to MBD<sup>−1</sup>, MBD<sup>−2</sup>, likely assists in copper delivery to the ATPase core. Invariant Tyr, Asn and Ser residues in the transmembrane domain assist in positioning sulfur-providing copper-binding amino acids, allowing for copper uptake, binding and release. As such, our findings unify previously conflicting data on the transport and regulation of P<sub>1B-1</sub>-ATPases. The results are critical for a fundamental understanding of cellular copper homeostasis and for comprehension of the molecular bases of P<sub>1B-1</sub>-disorders and ongoing clinical trials.</p>}}, author = {{Guo, Zongxin and Orädd, Fredrik and Bågenholm, Viktoria and Grønberg, Christina and Ma, Jian Feng and Ott, Peter and Wang, Yong and Andersson, Magnus and Pedersen, Per Amstrup and Wang, Kaituo and Gourdon, Pontus}}, issn = {{2041-1723}}, language = {{eng}}, number = {{1}}, publisher = {{Nature Publishing Group}}, series = {{Nature Communications}}, title = {{Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases}}, url = {{http://dx.doi.org/10.1038/s41467-024-47001-4}}, doi = {{10.1038/s41467-024-47001-4}}, volume = {{15}}, year = {{2024}}, }