Structural highlights
Publication Abstract from PubMedCopper 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. Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases.,Guo Z, Oradd F, Bagenholm V, Gronberg C, Ma JF, Ott P, Wang Y, Andersson M, Pedersen PA, Wang K, Gourdon P Nat Commun. 2024 Mar 27;15(1):2690. doi: 10.1038/s41467-024-47001-4. PMID:38538615[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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