Structures of the human Wilson disease copper transporter ATP7B

Yang, Guo-Min; Xu, Li; Wang, Rou-Min; Tao, Xin; Zheng, Zi-Wei; Chang, Shenghai; Ma, Demin; Zhao, Cheng; Dong, Yi; Wu, Shan; Guo, Jiangtao; Wu, Zhi‐Ying

doi:10.1016/j.celrep.2023.112417

Cited by 21 publications

(12 citation statements)

References 62 publications

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“…16 ). It is also consistent with the E1 state data of hATP7B, which displayed non-core ATPase cryo-EM density at the MB’ platform, also in the absence of ATOX1 (PDB-ID 8IOY 33 ), although this aspect was interpreted as MBD −1 (Supplementary Fig. 17 ) 33 .…”

Section: Resultssupporting

confidence: 85%

“…It is also consistent with the E1 state data of hATP7B, which displayed non-core ATPase cryo-EM density at the MB’ platform, also in the absence of ATOX1 (PDB-ID 8IOY 33 ), although this aspect was interpreted as MBD −1 (Supplementary Fig. 17 ) 33 . As we have already determined that MBD −1 is firmly anchored to the A-domain, the well-defined ferredoxin shape located at the MB’ platform in the chaperone-free E1 structure of hATP7B is here reinterpreted as MBD −2 , providing experimental support that MBD −2 can dock to the ion uptake region in the E1 conformation.…”

Section: Resultssupporting

confidence: 85%

“…Indeed, inspection of the available cryo-EM maps suggest it also occupies this position in previously determined hATP7B E1 structures, but relatively low resolution can explain why a feature at the MB’ platform was instead interpreted as MBD −1 (see further below, Supplementary Fig. 17 ) 33 . Thus, our and previous data together indicate a previously undiscovered location of MBD −1 in association with the A-domain that is preserved throughout the transport cycle, and likely broadly conserved across eukaryotic P 1B -ATPases.…”

Section: Resultsmentioning

confidence: 93%

“…It has previously been proposed that ATP turn-over of the soluble domains in P 1B -ATPases is different from other P-type ATPase classes, but the validity of these studies could be questioned considering the spread in origin of the compared members and because different experimental techniques have been used to obtain the structures 23 – 26 , 33 . Our HMA4 structures clearly support that the E1, but not E2P, conformation of P 1B-1 -ATPases is unique.…”

Section: Resultsmentioning

confidence: 99%

“…Hitherto, structural information on Cu + -ATPases is limited to the E2P and a subsequent E2.P i transition state of dephosphorylation of CopA from Legionella pneumophila (LpCopA) 23 , 25 , the E2P state of ATP7B from Xenopus tropicalis (XtATP7B) 24 , and an E1 state of CopA from Archaeoglobus fulgidus (AfCopA) and hATP7B 26 , 33 . These structures generally lack the MBDs, but the structural information for XtATP7B revealed the presence of the two MBDs closest to the core, MBD −2 and MBD −1 (previously MBD5 and MBD6, respectively), while the hATP7B structure displayed presence of one MBD (see more below).…”

Section: Introductionmentioning

confidence: 99%

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

Guo,

Orädd,

Bågenholm

et al. 2024

Nat Commun

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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.

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Section: Resultssupporting

confidence: 85%

Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Guo,

Orädd,

Bågenholm

et al. 2024

Nat Commun

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Structural Basis of Ion Transport in Copper‐Transporting P _IB ‐Type ATPases

Bågenholm,

Gourdon

2024

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Maintaining correct copper levels is vital for all cells, as copper is required for a large number of cellular processes, but is also toxic due to its high reactivity. Such regulation is accomplished using a range of processes, including the P IB‐1 ‐subgroup of P‐type ATPases. These primary active transporters exploit ATP to shuttle copper across cellular membranes, either out of the cell or into various organelles for cellular use, such as incorporation into copper‐dependent proteins. The pumping of copper across the membrane follows a conserved scheme, called the Post‐Albers cycle, where the protein cycles through a series of states, from inward‐open (E1) to inward‐occluded (E1P), outward‐open (E2P), and outward‐occluded (E2) and back, coupled to phosphorylation by ATP and dephosphorylation. This is established via a conserved core consisting of three soluble A‐, P‐, and N‐domains, and a transmembrane domain formed by eight membrane‐spanning helices, MA, MB, and M1–M6, as well as a varying number of metal‐binding domains MBDs, which typically are part of the N‐terminus. Copper is delivered to the P IB‐1 ‐transporter from small molecule or protein copper chaperones inside the cytoplasm, likely assisted by an MBD. The metal is then transferred to a methionine of M1 at the membrane interface, which relocates it to two conserved cysteines of the CPC motif in M4. Next, one or two high‐affinity‐binding sites are established in the M‐domain, again utilizing cysteines and methionines. Finally, release is achieved via an outward‐facing exit tunnel lined by methionines. While much of this pathway has been elucidated through determined molecular structures, important questions remain, for example, regarding the number of high‐affinity‐binding sites and the roles of the MBDs. Here, the structural details of the transport of copper through P IB‐1 ‐type ATPases will be described.

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Chaperon‐Abgeleitete Kupfer(I)‐Bindende Peptidnanofibrillen stören die Kupferhomöostase in Krebszellen

Jeena,

Link,

Zhang

et al. 2024

Angewandte Chemie

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Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu+ homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu+ homeostasis in cancer cells are rarely explored because small molecule Cu+ chelators have poor binding affinity in comparison to the intracellular Cu+ chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu+ chaperone‐inspired supramolecular approach to disrupt Cu+ homeostasis in cancer cells that induces programmed cell death. The Nap‐FFMTCGGCR peptide self‐assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu+ due to the presence of the unique MT/CGGC motif, which is conserved in intracellular Cu+ chaperones. Nap‐FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells (MDA‐MB‐231), impairs the activity of Cu+ dependent co‐chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap‐FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self‐assembly and Cu+ binding must work in synergy to successfully disrupt Cu+ homeostasis. We show that assembly‐enhanced affinity for metal ions opens new therapeutic strategies to address disease‐relevant metal ion homeostasis.

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Structures of the human Wilson disease copper transporter ATP7B

Cited by 21 publications

References 62 publications

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

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

Structural Basis of Ion Transport in Copper‐Transporting P _IB ‐Type ATPases

Chaperon‐Abgeleitete Kupfer(I)‐Bindende Peptidnanofibrillen stören die Kupferhomöostase in Krebszellen

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Structures of the human Wilson disease copper transporter ATP7B

Cited by 21 publications

References 62 publications

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

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

Structural Basis of Ion Transport in Copper‐Transporting P IB ‐Type ATPases

Chaperon‐Abgeleitete Kupfer(I)‐Bindende Peptidnanofibrillen stören die Kupferhomöostase in Krebszellen

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Structural Basis of Ion Transport in Copper‐Transporting P _IB ‐Type ATPases