Copper-Transfer Mechanism from the Human Chaperone Atox1 to a Metal-Binding Domain of Wilson Disease Protein

Rodriguez-Granillo, Agustina; Crespo, Alejandro; Estrin, Darı́o A.; Wittung-Stafshede, Pernilla

doi:10.1021/jp911208z

Cited by 43 publications

(63 citation statements)

References 47 publications

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“…The direct contribution is possible for apo–holo Hah1–MBD4 interactions, in which one Cu 1+ is coordinated by cysteine ligands from both interacting partners, as described in the thiol ligand exchange mechanism for copper chaperone mediated copper transfer 5, 19, 43. This metal-bridging was directly shown by the NMR structure of a Cu 1+ -bridged complex between Hah1 and a MBD of MNK protein (Figure 6)50 and the structural studies of related systems,20, 43, 51 as well as was supported by computational studies 52. This Cu 1+ bridging is not applicable for holo–holo interactions, though, as both proteins here would have Cu 1+ bound at their CXXC sites; consistently, no stabilization of protein complexes is observed in holo–holo Hah1–MBD4 interactions (Figure 4C).…”

Section: Discussionmentioning

confidence: 65%

Relating dynamic protein interactions of metallochaperones with metal transfer at the single-molecule level

et al. 2011

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SummaryMetallochaperones undertake specific interactions with their target proteins to deliver metal ions inside cells. Understanding how these protein interactions are coupled with the underlying metal transfer process is important, but challenging because they are weak and dynamic. Here we use a nanovesicle trapping scheme to enable single-molecule FRET measurements of the weak, dynamic interactions between the copper chaperone Hah1 and the fourth metal binding domain (MBD4) of WDP. By monitoring the behaviors of single interacting pairs, we visualize their interactions in real time in both the absence and the presence of various equivalents of Cu 1+ . Regardless of the proteins' metallation state, we observe multiple, interconverting interaction complexes between Hah1 and MBD4. Within our experimental limit, the overall interaction geometries of these complexes appear invariable, but their stabilities are dependent on the proteins' metallation state. In apo-holo Hah1-MBD4 interactions, the complexes are stabilized relative to that observed in the apo-apo interactions. This stabilization is undiscernible when Hah1's Cu 1+ -binding is eliminated or when both proteins have Cu 1+ loaded. The nature of this Cu 1+ -induced complex stabilization and of the interaction complexes are discussed. These Cu 1+ -induced effects on the Hah1-MBD4 interactions provide a step toward understanding how the dynamic protein interactions of copper chaperones are coupled with their metal transfer function.

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Section: Discussionmentioning

confidence: 65%

Relating dynamic protein interactions of metallochaperones with metal transfer at the single-molecule level

et al. 2011

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“…Using a computational approach and employing quantum mechanics/molecular mechanics methods to examine the molecular mechanism of protein-mediated Cu + transfer from the human Cu chaperone Atox1 to the fourth metal-binding domains of Wilson’s disease protein, Rodriguez-Granillo et al (2010) found that both Atox1 and Wilson’s disease protein have solvent-exposed metal-binding motifs with two Cys residues that coordinate Cu + . Those data suggest that the Cu-transfer reaction from Atox1 to Wilson’s disease protein appears to be kinetically accessible, and that altered protein-metal interaction in the nerve system may play a role on Cu toxicity.…”

Section: Cu Toxicitymentioning

confidence: 99%

Copper: toxicological relevance and mechanisms

2014

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Copper (Cu) is a vital mineral essential for many biological processes. The vast majority of all Cu in healthy humans is associated with enzyme prosthetic groups or bound to proteins. Cu homeostasis is tightly regulated through a complex system of Cu transporters and chaperone proteins. Excess or toxicity of Cu, which is associated with the pathogenesis of hepatic disorder, neurodegenerative changes and other disease conditions, can occur when Cu homeostasis is disrupted. The capacity to initiate oxidative damage is most commonly attributed to Cu-induced cellular toxicity. Recently, altered cellular events, including lipid metabolism, gene expression, alpha-synuclein aggregation, activation of acidic sphingomyelinase and release of ceramide, and temporal and spatial distribution of Cu in hepatocytes, as well as Cu-protein interaction in the nerve system, have been suggested to play a role in Cu toxicity. However, whether these changes are independent of, or secondary to, an altered cellular redox state of Cu remain to be elucidated.

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“…In the excretion pathway leading to the blood, copper is delivered to the trans-Golgi network by ATOX1, and transported across by ATP7B located on the trans-Golgi membrane. Copper is transferred as a Cu(I) ion from ATOX1 to the fourth metal binding domain of ATP7B [24]. Once in the trans-Golgi network, copper is incorporated into apo-ceruloplasmin, reduced to holo-ceruloplasmin, and then excreted as ceruloplasmin into the blood.…”

Section: Copper Homeostasismentioning

confidence: 99%

Inherited Copper Transport Disorders: Biochemical Mechanisms, Diagnosis, and Treatment

Kodama

Fujisawa²,

Bhadhprasit³

2012

CDM

158

151

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Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson’s disease. Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome.Wilson’s disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson’s disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson’s disease should be implemented in infants. Patients with Wilson’s disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson’s disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.

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Copper-Transfer Mechanism from the Human Chaperone Atox1 to a Metal-Binding Domain of Wilson Disease Protein

Cited by 43 publications

References 47 publications

Relating dynamic protein interactions of metallochaperones with metal transfer at the single-molecule level

Relating dynamic protein interactions of metallochaperones with metal transfer at the single-molecule level

Copper: toxicological relevance and mechanisms

Inherited Copper Transport Disorders: Biochemical Mechanisms, Diagnosis, and Treatment

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