ATPase ATP7B Research Articles

SP1/CTR1-mediated oxidative stress-induced cuproptosis in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is an age-related disease and is responsible for low back pain. Oxidative stress-induced cell death plays a fundamental role in IDD pathogenesis. Cuproptosis is a recently discovered form of programmed cell death dependent on copper availability. Whether cuproptosis is involved in IDD progression remains unknown. Herein, we established in vitro and in vivo models to investigate cuproptosis in IDD and the mechanisms by which oxidative stress interacts with copper sensitivity in nucleus pulposus cells (NPCs). We found that ferredoxin-1 (FDX1) content increased in both rat and human degenerated discs. Sublethal oxidative stress on NPCs led to increased FDX1 expression, tricarboxylic acid (TCA) cycle-related proteins lipoylation and aggregation, and cell death in the presence of Cu2+ at physiological concentrations, while FDX1 knockdown inhibited cell death. Since copper homeostasis is involved in copper-induced cytotoxicity, we investigated the role of copper transport-related proteins, including importer (CTR1) and efflux pumps (ATPase transporter, ATP7A, and ATP7B). CTR1 and ATP7A content increased under oxidative stress, and blocking CTR1 reduced oxidative stress/copper-induced TCA-related protein aggregation and cell death. Moreover, oxidative stress promoted the expression of specific protein 1 (SP1) and SP1-mediated CTR1 transcription. SP1 inhibition decreased cell death rates, preserved disc hydration, and alleviated tissue degeneration. This suggests that oxidative stress upregulates FDX1 expression and copper flux through promoting SP1-mediated CTR1 transcription, leading to increased TCA cycle-related protein aggregation and cuproptosis. This study highlights the importance of cuproptosis in IDD progression and provides a promising therapeutic target for IDD treatment.

Structures of the human Wilson disease copper transporter ATP7B

The P-type ATPase ATP7B exports cytosolic copper and plays an essential role in the regulation of cellular copper homeostasis. Mutants of ATP7B cause Wilson disease (WD), an autosomal recessive disorder of copper metabolism. Here, we present cryoelectron microscopy (cryo-EM) structures of human ATP7B in the E1 state in the apo, the putative copper-bound, and the putative cisplatin-bound forms. In ATP7B, the N-terminal sixth metal-binding domain (MBD6) binds at the cytosolic copper entry site of the transmembrane domain (TMD), facilitating the delivery of copper from the MBD6 to the TMD. The sulfur-containing residues in the TMD of ATP7B mark the copper transport pathway. By comparing structures of the E1 state human ATP7B and E2-Pi state frog ATP7B, we propose the ATP-driving copper transport model of ATP7B. These structures not only advance our understanding of the mechanisms of ATP7B-mediated copper export but can also guide the development of therapeutics for the treatment of WD.

Copper-dependent ATP7B N-terminal domain dynamics in two reaction-cycle intermediates

Membrane proteins control the flow of ions across biological membranes by selective import or export and are of vital importance for all living cells. Disturbances in ion transport can cause severe diseases such as Wilson’s disease, which is caused by mutations in the human copper-transporting P-type ATPase ATP7B. ATP7B activity is regulated by a dynamic N-terminal domain consisting of six metal binding domains (MBDs) that move as rigid bodies and interact transiently with each other and the core transporter in a copper-dependent manner.

The molecular and cellular basis of copper dysregulation and its relationship with human pathologies.

Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.

English

Wilson’s disease (WD) is a genetic disorder characterised by mutations in copper metabolism. Adenosine triphosphate (ATPase) ATP7B gene is responsible for disturbance in copper metabolism that leads to accumulation of copper mainly in liver and also in extra hepatic organs (like brain, cornea, heart and kidney).1 Heavy metal accumulation in brain (mainly in basal ganglia) leads to neuropsychiatric manifestations.2 Kayser Fleischer (KF) ring is golden brown ring distributed along the periphery of cornea. It is due to abnormal deposition of copper in the Descemet’s membrane of cornea. Kayser Fleischer (KF) ring is a pathognomonic sign of Wilson’s disease. Fulminant hepatic failure can be the first presentation of WD. Patients presenting with fulminant Wilson’s disease (FWD) clinically present as acute liver failure with encephalopathy and coagulopathy. The mortality of patients is high and orthotropic liver transplantation is the only option, which has been shown effective in patients with Fulminant Wilson’s disease.3 We are report a case of a young male who presented as acute liver failure first time in life and later was diagnosed as FWD.

Reverse regulation of hepatic ceruloplasmin production in rat model of myocardial ischemia

BackgroundCeruloplasmin (Cp) is a major copper-binding protein produced in the liver and delivers copper to extrahepatic organs. Patients with myocardial infarction are often featured by an elevation of serum copper concentrations due to copper efflux from ischemic hearts. The present study was undertaken to test the hypothesis that serum copper elevation leads to up-regulation of hepatic Cp in myocardial infarction. MethodsAdult male Sprague-Dawley rats were subjected to left anterior descending (LAD) coronary artery ligation to induce myocardial infarction. Serum copper and Cp levels, as well as changes in hepatic Cp and copper-transporting P-type ATPase (Atp7b), were determined from blood and liver samples collected on day 1, 4, or 7 after the operation. ResultsSerum copper concentrations were significantly increased on day 4 after LAD ligation, accompanied by an increase in serum Cp levels and activities. Concomitantly, the protein levels of Cp and copper exporter, Atp7b, were also significantly increased in the liver. Furthermore, inhibiting the increase of serum copper by a copper chelator, triethylenetetramine (TETA), effectively abolished the elevated Cp activity after LAD ligation. ConclusionThese results indicate that serum Cp elevation in response to myocardial ischemia most likely resulted from the increased hepatic Cp production, which in turn was more responsive to serum copper elevation than inflammatory response following myocardial ischemia.

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance.

Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute.

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

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 P1B-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.

Changes in mammalian copper homeostasis during microbial infection.

Animals carefully control homeostasis of Cu, a metal that is both potentially toxic and an essential nutrient. During infection, various shifts in Cu homeostasis can ensue. In mice infected with Candida albicans, serum Cu progressively rises and at late stages of infection, liver Cu rises, while kidney Cu declines. The basis for these changes in Cu homeostasis was poorly understood. We report here that the progressive rise in serum Cu is attributable to liver production of the multicopper oxidase ceruloplasmin (Cp). Through studies using Cp-/- mice, we find this elevated Cp helps recover serum Fe levels at late stages of infection, consistent with a role for Cp in loading transferrin with Fe. Cp also accounts for the elevation in liver Cu seen during infection, but not for the fluctuations in kidney Cu. The Cu exporting ATPase ATP7B is one candidate for kidney Cu control, but we find no change in the pattern of kidney Cu loss during infection of Atp7b-/- mice, implying alternative mechanisms. To test whether fungal infiltration of kidney tissue was required for kidney Cu loss, we explored other paradigms of infection. Infection with the intravascular malaria parasite Plasmodium berghei caused a rise in serum Cu and decrease in kidney Cu similar to that seen with C. albicans. Thus, dynamics in kidney Cu homeostasis appear to be a common feature among vastly different infection paradigms. The implications for such Cu homeostasis control in immunity are discussed.

Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs.

Membrane trafficking pathways emanating from the Golgi regulate a wide range of cellular processes. One of these is the maintenance of copper (Cu) homeostasis operated by the Golgi-localized Cu-transporting ATPases ATP7A and ATP7B. At the Golgi, these proteins supply Cu to newly synthesized enzymes which use this metal as a cofactor to catalyze a number of vitally important biochemical reactions. However, in response to elevated Cu, the Golgi exports ATP7A/B to post-Golgi sites where they promote sequestration and efflux of excess Cu to limit its potential toxicity. Growing tumors actively consume Cu and employ ATP7A/B to regulate the availability of this metal for oncogenic enzymes such as LOX and LOX-like proteins, which confer higher invasiveness to malignant cells. Furthermore, ATP7A/B activity and trafficking allow tumor cells to detoxify platinum (Pt)-based drugs (like cisplatin), which are used for the chemotherapy of different solid tumors. Despite these noted activities of ATP7A/B that favor oncogenic processes, the mechanisms that regulate the expression and trafficking of Cu ATPases in malignant cells are far from being completely understood. This review summarizes current data on the role of ATP7A/B in the regulation of Cu and Pt metabolism in malignant cells and outlines questions and challenges that should be addressed to understand how ATP7A and ATP7B trafficking mechanisms might be targeted to counteract tumor development.

From and to the Golgi – defining the Wilson disease protein road map

Recent studies highlight the continued growth in the identification of a variety of cellular functions that involve the Golgi apparatus. Apart from well-known membrane sorting/trafficking and glycosylation machineries, the Golgi harbors molecular platforms operating in intracellular signaling, cytoskeleton organization, and protein quality control mechanisms. One of new emerging Golgi functions consists in the regulation of copper homeostasis by coordinating the relocation and activity of copper transporters. Of these, the Cu-transporting ATPase ATP7B (known as Wilson disease protein) plays a key role in the maintenance of the Cu balance in the body via the supply of essential Cu to the systemic circulation and via elimination of excess Cu into the bile. These activities require tightly regulated shuttling of ATP7B between the Golgi and different post-Golgi compartments. Despite significant progress over recent years, a number of issues regarding ATP7B trafficking remain to be clarified. This review summarizes current views on ATP7B trafficking pathways from and to the Golgi and underscores the challenges that should be addressed to define the ATP7B trafficking routes and mechanisms in health and disease.

Mechanistic and Structural Basis for Inhibition of Copper Trafficking by Platinum Anticancer Drugs.

Copper (Cu) is required for maturation of cuproenzymes, cell proliferation, and angiogenesis, and its transport entails highly specific protein-protein interactions. In humans, the Cu chaperone Atox1 mediates Cu(I) delivery to P-type ATPases Atp7a and Atp7b (the Menkes and Wilson disease proteins, respectively), which are responsible for Cu release to the secretory pathway and excess Cu efflux. Cu(I) handover is believed to occur through the formation of three-coordinate intermediates where the metal ion is simultaneously linked to Atox1 and to a soluble domain of Cu-ATPases, both sharing a CxxC dithiol motif. The ultrahigh thermodynamic stability of chelating S-donor ligands secures the redox-active and potentially toxic Cu(I) ion, while their kinetic lability allows facile metal transfer. The same CxxC motifs can interact with and mediate the biological response to antitumor platinum drugs, which are among the most used chemotherapeutics. We show that cisplatin and an oxaliplatin analogue can specifically bind to the heterodimeric complex Atox1-Cu(I)-Mnk1 (Mnk1 is the first soluble domain of Atp7a), thus leading to a kinetically stable adduct that has been structurally characterized by solution NMR and X-ray crystallography. Of the two possible binding configurations of the Cu(I) ion in the cage made by the CxxC motifs of the two proteins, one (bidentate Atox1 and monodentate Mnk1) is less stable and more reactive toward cis-Pt(II) compounds, as shown by using mutated proteins. A Cu(I) ion can be retained at the Pt(II) coordination site but can be released to glutathione (a physiological thiol) or to other complexing agents. The Pt(II)-supported heterodimeric complex does not form if Zn(II) is used in place of Cu(I) and transplatin instead of cisplatin. The results indicate that Pt(II) drugs can specifically affect Cu(I) homeostasis by interfering with the rapid exchange of Cu(I) between Atox1 and Cu-ATPases with consequences on cancer cell viability and migration.

Copper Sulfide Facilitates Hepatobiliary Clearance of Gold Nanoparticles through the Copper-Transporting ATPase ATP7B.

Metallic gold (Au) nanoparticles have great potential for a wide variety of biomedical applications. Yet, slow clearance of Au nanoparticles significantly hinders their clinical translation. Herein, we describe a strategy of utilizing the endogenous copper (Cu) clearance to improve the elimination of Au nanoparticles. Our mechanistic study reveals that a Cu-transporting P-type ATPase, ATP7B, mediates the exocytosis of CuS nanoparticles into bile canaliculi for their rapid hepatobiliary excretion. The efflux of CuS nanoparticles is adopted to facilitate the hepatobiliary clearance of Au nanoparticles through CuS-Au conjugation. Using two different CuS-Au nanoconjugates, we demonstrate that CuS increases the biliary Au excretion of CuS-Au nanospheres or CuS-Au nanorods in mice or rats in comparison to that of their respective unconjugated Au nanoparticles postintravenous injection. The current CuS-Au conjugation approach provides a feasible strategy to enhance the hepatobiliary clearance of Au nanoparticles that may be applicable to various structures.

A Gene Therapy Approach to Improve Copper Metabolism and Prevent Liver Damage in a Mouse Model of Wilson Disease.

Wilson disease (WD), an autosomal recessive disease caused by mutations in a copper-transporting P-type ATPase (Atp7b), causes severe liver damage. This disease is currently treated with the lifelong use of copper chelation therapy, which has side effects and does not fix copper metabolism. Here, we thoroughly characterized a mouse model of WD, the toxic milk mouse, and used the model to test a gene therapy approach for treating WD. WD mice accumulated copper in the liver from birth; severe copper accumulation and concurrent liver disease were evident by 2 months of age. Intravenously administering an adeno-associated viral (AAV) 8 vector expressing a codon-optimized version of the human ATP7B transgene into 2-month-old WD mice significantly decreased liver copper levels compared with age-matched, uninjected, WD mice. We also observed a significant dose-dependent decrease in liver disease. Male mice injected with 1011 genome copies of AAV8 vector showed only mild histopathological findings with a complete lack of liver fibrosis. Therefore, we conclude that administering gene therapy at the early stages of disease onset is a promising approach for reducing liver damage and correcting copper metabolism in WD.

A Luminal Loop of Wilson Disease Protein Binds Copper and Is Required for Protein Activity

The copper-transporting ATPase ATP7B is essential for loading of copper ions to copper-dependent enzymes in the secretory pathway; its inactivation results in Wilson disease. In contrast to copper-ion uptake by the cytoplasmic domains, ATP7B-mediated copper-ion release in the Golgi has not been explored yet. We demonstrate here that a luminal loop in ATP7B, rich in histidine/methionine residues, binds reduced copper (Cu(I)) ions, and identified copper-binding residues play an essential role in ATP7B-mediated metal ion release. NMR experiments on short-peptide models demonstrate that three methionine and two histidine residues are specifically involved in Cu(I) ion binding; with these residues replaced by alanines, no Cu(I) ion interaction is detected. Although more than one Cu(I) ion can interact with the wild-type peptide, removing either all histidine or all methionine residues reduces the stoichiometry to one Cu(I) ion binding per peptide. Using a yeast complementation assay, we show that for efficient copper transport by full-length ATP7B, the complete set of histidine and methionine residues in the lumen loop are required. The replacement of histidine/methionine residues by alanines does not perturb overall ATP7B structure, as the localization of ATP7B variants in yeast cells matches that of the wild-type protein. Thus, in similarity to ATP7A, ATP7B also appears to have a luminal “exit” copper ion site.

Brain copper storage after genetic long-term correction in a mouse model of Wilson disease.

Wilson disease is a rare autosomal recessive condition caused by mutations in the copper-transporting ATPase ATP7B gene (OMIM: 606882) provoking loss of function and resulting in variable hepatic and neurologic symptoms. Currently, the treatment of Wilson disease focuses on achieving a negative copper balance either with chelators (e.g., d-penicillamine, trientine, and tetrathiomolybdate) or zinc, which reduces copper absorption, or a combination thereof.1 However, these lifelong treatment regimens often cause side effects and do not restore normal copper metabolism. The authors thank Astrid Kuppers (Zentralinstitut fur Engineering, Elektronik und Analytik, Forschungszentrum Julich, Julich, Germany) for excellent technical assistance in LA-ICP-MS measurements. They acknowledge Drs Nick Weber and Bernard Benichou for critical comments and careful review and Dr. Andreas Matusch (Division of Molecular Neuroimaging, Institute of Neuroscience and Medicine-2, Forschungszentrum Julich, Germany) for help in preparing murine brains.

ATP7B rs9535826 is associated with gastrointestinal toxicity of platinum-based chemotherapy in nonsmall cell lung cancer patients

Platinum-based chemotherapy is considered as the first-line treatment for nonsmall cell lung cancer (NSCLC) patients. However, platinum resistance and toxicity are major obstacles to its clinical applications. The two P-type ATPases ATP7A and ATP7B have been identified to play an essential role in the transport of platinum. Their genetic polymorphisms may affect the treatment outcome and toxicity of platinum. In this study, we aimed to investigate the association of ATP7A and ATP7B genetic polymorphisms with clinical outcome and toxicity of platinum-based chemotherapy in NSCLC patients. Four hundred and twenty-seven NSCLC patients were enrolled. All patients have accepted platinum-based chemotherapy for at least two cycles. ATP7A (rs2227291 and rs6622665) and ATP7B (rs1061472 and rs9535826) polymorphisms were genotyped by allele-specific matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Chemotherapeutic response, overall survival time, and hematological and gastrointestinal toxicity were recorded and their associations with genetic factors were evaluated. ATP7A rs2227291 and rs6622665 deviated from Hardy-Weinberg equilibrium. Therefore, the two single-nucleotide polymorphisms were not taken into consideration. For ATP7B polymorphism, ATP7B rs9535826 was associated with gastrointestinal toxicity, and the GG genotype showed lower gastrointestinal toxicity (odds ratio = 0.30; 95% confidence interval = 0.10-0.90; P = 0.031). The genotypes of ATP7B gene may be novel and significant biomarkers for predicting the gastrointestinal toxicity of platinum-based chemotherapy in NSCLC patients.

Mechanisms of charge transfer in human copper ATPases ATP7A and ATP7B.

ATP7A and ATP7B are Cu+ -transporting ATPases of subclass IB and play a fundamental role in intracellular copper homeostasis. ATP7A/B transfer Cu+ ions across the membrane from delivery to acceptor proteins without establishing a free Cu+ gradient. Transfer of copper across the membrane is coupled to ATP hydrolysis. Current measurements on solid supported membranes (SSM) were performed to investigate the mechanism of copper-related charge transfer across ATP7A and ATP7B. SSM measurements demonstrated that electrogenic copper displacement occurs within ATP7A/B following addition of ATP and formation of the phosphorylated intermediate. Comparison of the time constants for cation displacement in ATP7A/B and sarcoplasmic reticulum Ca2+ -ATPase is consistent with the slower phosphoenzyme formation in copper ATPases. Moreover, ATP-dependent copper transfer in ATP7A/B is not affected by varying the pH, suggesting that net proton counter-transport may not occur in copper ATPases. Platinum anticancer drugs activate ATP7A/B and are subjected to ATP-dependent vectorial displacement with a mechanism analogous to that of copper. © 2016 IUBMB Life, 69(4):218-225, 2017.

Chapter 5 - Pathogenesis of Wilson disease

Wilson disease is an autosomal-recessive disorder originating from a genetic defect in the copper-transporting ATPase ATP7B that is required for biliary copper secretion and loading of ceruloplasmin with copper. Impaired ATP7B function in Wilson disease results in excessive accumulation of copper in liver, brain, and other tissues. Toxic copper deposits may induce oxidative stress, modify expression of genes, directly inhibit proteins, and impair mitochondrial function, leading to hepatic, neuropsychiatric, renal, musculoskeletal, and other symptoms. Hepatocyte dysfunction initially manifests as steatosis and later may progress to other hepatic phenotypes such as acute liver failure, hepatitis, and fibrosis. In the brain, copper accumulates in astrocytes, leading to impairment of the blood-brain barrier and consequent damage to neurons and oligodendrocytes. Basal ganglia and brainstem are the brain regions with highest susceptibility to copper toxicity and their lesions lead to various combinations of movement and psychiatric disorders. This chapter will give an overview of the essential requirement of copper for biologic processes and the molecular mechanisms employed by cells to maintain their copper levels in a proper range. We will specify the physiologic functions of ATP7B and the consequences of its dysfunction and summarize the current knowledge on the pathogenesis of liver and neuropsychiatric disease. Finally, we will describe the consequences of copper overload in Wilson disease in other tissues.

Molecular features of copper binding proteins involved in copper homeostasis.

Copper has a wide and important role in biological systems, determining conformation and activity of many metalloproteins and enzymes, such as cytochrome oxidase and superoxide dismutase . Furthermore, due to its possible reactivity with nonspecific proteins and toxic effects, elaborate systems of absorption, concentration buffering, delivery to specific protein sites and elimination, require a complex system including small carriers, chaperones and active transporters. The P-type copper ATPases ATP7A and ATP7B provide an important system for acquisition, active transport, distribution and elimination of copper. Relevance of copper metabolism to human diseases and therapy is already known. It is quite certain that further studies will reveal detailed and useful information on biochemical mechanisms and relevance to diseases. © 2016 IUBMB Life, 69(4):211-217, 2017.