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

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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.
OriginalsprogEngelsk
Artikelnummer2690
TidsskriftNature Communications
Vol/bind15
Udgave nummer1
Antal sider16
ISSN2041-1723
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
This study was supported by The Lundbeck Foundation (R322-2019-2588; V.B., R133-A12689; K.W., R133-A12689, R218-2016-1548, R313-2019-774 and R346-2020-2019; P.G.), The Novo Nordisk Foundation (NNF16OC0021272 and 0078574; P.G.), the Danish Council for Independent Research (6108-00479 and 9039-00273; P.G.), the Swedish Research Council (2020-03840; M.A., 2016-04474 and 2022-01315; P.G.), Knut and Alice Wallenberg Foundation (2015.0131 and 2020.0194; P.G.), the Crafoord Foundation (20170818, 20180652 and 20200739; P.G.), The Carlsberg Foundation (CF15-0542 and CF21-0647; P.G.), the Per-Eric and Ulla Schybergs Foundation (38267; P.G.), the Augustinus Foundation for equipment (16-1992; P.G.,), the Brødrene Hartmanns Foundation (A29519; P.G.), the Agnes and Poul Friis Foundation (n/a; P.G.), as well as by the Japan Society for the Promotion of Science (21H05034; J.F.M.). The post-doc fellowship of CG was supported by The BRIDGE - Translational Excellence Programme at University of Copenhagen funded by the Novo Nordisk Foundation. C.G. was also financially assisted by The memorial foundation of manufacturer Vilhelm Pedersen and wife—and the Aarhus Wilson consortium. Computational resources were provided by the Swedish National Infrastructure for Computing (SNIC) through the High-Performance Computing Center North (HPC2N) under project SNIC 2022/5-168 and by the High-Performance Computing Center North (HPC2N) under project hpc2n2023-005. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank Tillmann Hanns Pape at the Danish Cryo-EM Facility at the Core Facility for Integrated Microscopy (CFIM) at University of Copenhagen for assistance with sample screening and data collection. The Danish Cryo-EM Facility at CFIM, University of Copenhagen is supported by Novo-Nordisk Foundation grant no. NNF14CC0001. We would also like to thank Julian Conrad, Karin Wallden, Dustin Morado and Marta Carroni at the Cryo-EM Swedish National Facility in Stocholm for sample screening and data collection. The Cryo-EM Swedish National Facility at SciLifeLab is funded by the Knut and Alice Wallenberg, Family Erling Persson and Kempe Foundations, SciLifeLab, Stockholm University and Umeå University.

Publisher Copyright:
© The Author(s) 2024.

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