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

Author:

Guo ZongxinORCID,Orädd FredrikORCID,Bågenholm Viktoria,Grønberg Christina,Ma Jian FengORCID,Ott PeterORCID,Wang YongORCID,Andersson MagnusORCID,Pedersen Per AmstrupORCID,Wang KaituoORCID,Gourdon PontusORCID

Abstract

AbstractCopper 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.

Funder

Lundbeckfonden

Novo Nordisk Fonden

Det Frie Forskningsråd

Vetenskapsrådet

Knut och Alice Wallenbergs Stiftelse

Crafoordska Stiftelsen

Publisher

Springer Science and Business Media LLC

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. In vitro reconstitution of transition metal transporters;Journal of Biological Chemistry;2024-08

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