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

Author

Listed:
  • Zongxin Guo

    (Copenhagen University)

  • Fredrik Orädd

    (Umeå University)

  • Viktoria Bågenholm

    (Copenhagen University)

  • Christina Grønberg

    (Copenhagen University)

  • Jian Feng Ma

    (Okayama University)

  • Peter Ott

    (Aarhus University Hospital)

  • Yong Wang

    (Zhejiang University)

  • Magnus Andersson

    (Umeå University)

  • Per Amstrup Pedersen

    (University of Copenhagen)

  • Kaituo Wang

    (Copenhagen University
    Chinese Academy of Sciences)

  • Pontus Gourdon

    (Copenhagen University
    Lund University)

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 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.

Suggested Citation

  • Zongxin Guo & Fredrik Orädd & Viktoria Bågenholm & Christina Grønberg & Jian Feng Ma & Peter Ott & Yong Wang & Magnus Andersson & Per Amstrup Pedersen & Kaituo Wang & Pontus Gourdon, 2024. "Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47001-4
    DOI: 10.1038/s41467-024-47001-4
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