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

Zongxin Guo, Fredrik Orädd, Viktoria Bågenholm, Christina Grønberg, Jian Feng Ma, Peter Ott, Yong Wang, Magnus Andersson, Per Amstrup Pedersen, Kaituo Wang () and Pontus Gourdon ()
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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
Pontus Gourdon: Copenhagen University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47001-4

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