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; Pontus Gourdon

doi:10.1038/s41467-024-47001-4

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^*, Pontus Gourdon^*

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin - Lever-, Mave- og Tarmsygdomme

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

2 Citationer (Scopus)

Abstract

Copper transporting P-type (P_1B-1-) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P_1B-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 P_1B-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 P_1B-1-ATPases. The results are critical for a fundamental understanding of cellular copper homeostasis and for comprehension of the molecular bases of P_1B-1-disorders and ongoing clinical trials.

Originalsprog	Engelsk
Artikelnummer	2690
Tidsskrift	Nature Communications
Vol/bind	15
Nummer	1
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-024-47001-4
Status	Udgivet - 27 mar. 2024

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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.",

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AU - Grønberg, Christina

AU - Ma, Jian Feng

AU - Ott, Peter

AU - Wang, Yong

AU - Andersson, Magnus

AU - Pedersen, Per Amstrup

AU - Wang, Kaituo

AU - Gourdon, Pontus

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

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