Dynamics of the metal binding domains and regulation of the human copper transporters ATP7B and ATP7A

Yu, Corey H.; Dolgova, Natalia V.; Dmitriev, Oleg Y.

doi:10.1002/iub.1611

Cited by 38 publications

(39 citation statements)

References 70 publications

(102 reference statements)

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“…For example, examinations via NMR of Cu(I) delivery from Cu(I)-Atox1 to the multidomain protein ATP7B MBDs 1-6 34 , the determination of the structures of the Atx1-Ccc2a 52 and complexes between Atox1 and the MBD1 of ATP7A from yeast and human, respectively 53 , all described the observed intermolecular adducts as metal-mediated. This is despite the fact that extensive intermolecular interfaces between the proteins in the complexes have been defined 52,53 , that the surface electrostatics of the proteins have been shown to be crucial for complex formation 53,56 and that only minimal structural differences have been observed between apo-and Cu(I)-forms of these proteins and domains 37,60 . However, NMR experiments have also demonstrated interactions between MBDs 4-6 of ATP7B and Atox1 in the absence of Cu 27 .…”

Section: Resultsmentioning

confidence: 99%

“…This finding suggests a potential redundancy in this system and a role for hGrx1 under cellular conditions where the activity of Atox1 in Cu regulation is attenuated. For example, a number of lines of evidence suggest that both the cellular ratios of apo-Atox1/Cu(I)-Atox1 and reduced/oxidized Atox1 influence metabolic Cu flux and specifically the activity and trafficking of the Cu ATPases 37,38,62 . There is also evidence to suggest that Atox1 is not absolutely required for Cu delivery to the Cu(I)-ATPases 59,63 and that other Cu carriers may supplement Atox1 function.…”

Section: Resultsmentioning

confidence: 99%

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Human glutaredoxin-1 can transfer copper to isolated metal binding domains of the P1B-type ATPase, ATP7B

Maghool

Fontaine

Roberts

et al. 2020

Sci Rep

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Intracellular copper (Cu) in eukaryotic organisms is regulated by homeostatic systems, which rely on the activities of soluble metallochaperones that participate in Cu exchange through highly tuned protein-protein interactions. Recently, the human enzyme glutaredoxin-1 (hGrx1) has been shown to possess Cu metallochaperone activity. The aim of this study was to ascertain whether hGrx1 can act in Cu delivery to the metal binding domains (MBDs) of the P 1B-type ATPase ATP7B and to determine the thermodynamic factors that underpin this activity. hGrx1 can transfer Cu to the metallochaperone Atox1 and to the MBDs 5-6 of ATP7B (WLN5-6). This exchange is irreversible. In a mixture of the three proteins, Cu is delivered to the WLN5-6 preferentially, despite the presence of Atox1. This preferential Cu exchange appears to be driven by both the thermodynamics of the interactions between the proteins pairs and of the proteins with Cu(I). Crucially, protein-protein interactions between hGrx1, Atox1 and WLN5-6 were detected by NMR spectroscopy both in the presence and absence of Cu at a common interface. This study augments the possible activities of hGrx1 in intracellular Cu homeostasis and suggests a potential redundancy in this system, where hGrx1 has the potential to act under cellular conditions where the activity of Atox1 in Cu regulation is attenuated. Copper (Cu) is a redox active metal and an essential trace element for human health 1,2. In biological systems, Cu is found in two oxidation states, reduced Cu(I) (cuprous) and oxidized Cu(II) (cupric). These reversible states, which allow Cu to serve as both an oxidant and reductant, render it an exceptional cofactor for redox enzymes known as oxidoreductases 1,2 , however excess intracellular concentrations of Cu are toxic and lead to cellular oxidative damage 3,4. In particular, the reaction of hydrogen peroxide with Cu(I) and the reduction of Cu(II) by superoxide, produce hydroxyl radicals that damage proteins, nucleic acids and lipids 5,6. In humans, the dysregulation of Cu metabolism is associated with diseases such as Menkes syndrome, Wilson's disease, prion diseases, Alzheimer's disease and fatal motor neuron diseases such as familial amyotrophic lateral sclerosis 7-12. To maintain the fine balance between cellular Cu requirements and toxicity, organisms have evolved sophisticated metalloregulatory systems for the coordination of metals such as Cu to proteins within the cell, and the controlled transfer of these metals between protein partners. Soluble proteins that are responsible for Cu binding and transfer are termed 'metallochaperones' 3 , which transport Cu in its reduced state (Cu(I)), often via coordination with cysteine residues 13,14. In eukaryotes, including humans, Cu concentrations are regulated through control of the levels of the Cu import protein, copper transporter 1 (Ctr1) 15,16 at the plasma membrane and the trafficking and/or activity of the Cu export proteins, ATP7A or ATP7B 17-19. In humans, ATP7A (Menkes disease protein, MNK) and ATP7B (Wilso...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Human glutaredoxin-1 can transfer copper to isolated metal binding domains of the P1B-type ATPase, ATP7B

Maghool

Fontaine

Roberts

et al. 2020

Sci Rep

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“…Studies of interactions between the N-terminal metal binding domains of the human copper transporters ATP7A and ATP7B, which contain six such domains, have revealed that, while domains 5 and 6 form a compact structure, overall, the six domains do not [15,21,32]. Instead, they undergo transient interactions with each other that are likely to be important for both copper transfer and for regulation of transfer activity [33]. In particular, domains 1-3 of ATP7A were shown to interact with each other in a highly dynamic, transient fashion [34], and very recent NMR studies of interactions between the separately purified domains showed a clear interaction between domains 1 and 3, and some evidence for weaker interactions between domains 1 and 2 and 2 and 3 [35].…”

Section: Discussionmentioning

confidence: 99%

The N-terminal domains of Bacillus subtilis CopA do not form a stable complex in the absence of their inter-domain linker

Zhou

Kay

Hecht

et al. 2018

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Copper-transporting P-type ATPases, which play important roles in trafficking Cu(I) across membranes for the biogenesis of copper proteins or for copper detoxification, contain a variable number of soluble metal-binding domains at their N-termini. It is increasingly apparent that these play an important role in regulating copper transport in a Cu(I)-responsive manner, but how they do this is unknown. CopA, a Cu(I)-transporter from Bacillus subtilis, contains two N-terminal soluble domains that are closely packed, with inter-domain interactions at two principal regions. Here, we sought to determine the extent to which the domains interact in the absence of their inter-domain covalent linker, and how their Cu(I)-binding properties are affected. Studies of a 1:1 mixture of separate CopAa and CopAb domains showed that the domains do not form a stable complex, with only indirect evidence of a weak interaction between them. Their Cu(I)-binding behaviour was distinct from that of the two domain protein and consistent with a lack of interaction between the domains. Cu(I)-mediated protein association was observed, but this occurred only between domains of the same type. Thus, the inter-domain covalent link between CopAa and CopAb is essential for inter-domain interactions and for Cu(I)-binding behaviour.

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“…Thus, there are several mechanisms for buffering, storing, and removing intracellular Cu. In mammals, two P‐type ATPases, ATP7A and ATP7B, have a prominent role in intracellular Cu homeostasis and transport (Lutsenko, ; Migocka, ; Yu et al., ). Mutations in ATP7A disrupt Cu absorption in the gut and intracellular delivery to Cu‐dependent enzymes, resulting in Menkes disease (Kaler, ; Lenartowicz et al., ; Zlatic et al., ).…”

Section: Introductionmentioning

confidence: 99%

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

Yamada

Prosser

2018

Eur J of Neuroscience

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The mammalian circadian clock in the suprachiasmatic nucleus (SCN) is very robust, able to coordinate our daily physiological and behavioral rhythms with exquisite accuracy. Simultaneously, the SCN clock is highly sensitive to environmental timing cues such as the solar cycle. This duality of resiliency and sensitivity may be sustained in part by a complex intertwining of three cellular oscillators: transcription/translation, metabolic/redox, and membrane excitability. We suggest here that one of the links connecting these oscillators may be forged from copper (Cu). Cellular Cu levels are highly regulated in the brain and peripherally, and Cu affects cellular metabolism, redox state, cell signaling, and transcription. We have shown that both Cu chelation and application induce nighttime phase shifts of the SCN clock in vitro and that these treatments affect glutamate, N‐methyl‐D‐aspartate receptor, and associated signaling processes differently. More recently we found that Cu induces mitogen‐activated protein kinase‐dependent phase shifts, while the mechanisms by which Cu removal induces phase shifts remain unclear. Lastly, we have found that two Cu transporters are expressed in the SCN, and that one of these transporters (ATP7A) exhibits a day/night rhythm. Our results suggest that Cu homeostasis is tightly regulated in the SCN, and that changes in Cu levels may serve as a time cue for the circadian clock. We discuss these findings in light of the existing literature and current models of multiple coupled circadian oscillators in the SCN.

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Dynamics of the metal binding domains and regulation of the human copper transporters ATP7B and ATP7A

Cited by 38 publications

References 70 publications

Human glutaredoxin-1 can transfer copper to isolated metal binding domains of the P1B-type ATPase, ATP7B

Human glutaredoxin-1 can transfer copper to isolated metal binding domains of the P1B-type ATPase, ATP7B

The N-terminal domains of Bacillus subtilis CopA do not form a stable complex in the absence of their inter-domain linker

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

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