Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases
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Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases. / Guo, Zongxin; Orädd, Fredrik; Bågenholm, Viktoria; Grønberg, Christina; Ma, Jian Feng; Ott, Peter; Wang, Yong; Andersson, Magnus; Pedersen, Per Amstrup; Wang, Kaituo; Gourdon, Pontus.
I: Nature Communications, Bind 15, Nr. 1, 2690, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases
AU - Guo, Zongxin
AU - Orädd, Fredrik
AU - Bågenholm, Viktoria
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
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - 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.
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.
U2 - 10.1038/s41467-024-47001-4
DO - 10.1038/s41467-024-47001-4
M3 - Journal article
C2 - 38538615
AN - SCOPUS:85188924528
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2690
ER -
ID: 387846815