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Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases

Guo, Zongxin ; Orädd, Fredrik ; Bågenholm, Viktoria ; Grønberg, Christina ; Ma, Jian Feng ; Ott, Peter ; Wang, Yong ; Andersson, Magnus ; Pedersen, Per Amstrup and Wang, Kaituo , et al. (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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
issue
1
article number
2690
publisher
Nature Publishing Group
external identifiers
  • scopus:85188924528
  • pmid:38538615
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
2024-04-30 12:16:01
@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}},
}