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1
Linz, Rachel, Natalie L. Barnes, Adriana M. Zimnicka, Jack H. Kaplan, Betty Eipper, and Svetlana Lutsenko. "Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b−/−kidney." American Journal of Physiology-Renal Physiology 294, no. 1 (2008): F53—F61. http://dx.doi.org/10.1152/ajprenal.00314.2007.
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Kidneys regulate their copper content more effectively than many other organs in diseases of copper deficiency or excess. We demonstrate that two copper-transporting ATPases, ATP7A and ATP7B, contribute to this regulation. ATP7A is expressed, to a variable degree, throughout the kidney and shows age-dependent intracellular localization. In 2-wk-old mice, ATP7A is located in the vicinity of the basolateral membrane, whereas in 20-wk-old mice, ATP7A is predominantly in intracellular vesicles. Acute elevation of serum copper, via intraperitoneal injection, results in the in vivo redistribution of ATP7A from intracellular compartments toward the basolateral membrane, illustrating a role for ATP7A in renal response to changes in copper load. Renal copper homeostasis also requires functional ATP7B, which is coexpressed with ATP7A in renal cells of proximal and distal origin. The kidneys of Atp7b−/−mice, an animal model of Wilson disease, show metabolic alterations manifested by the appearance of highly fluorescent deposits; however, in marked contrast to the liver, renal copper is not significantly elevated. The lack of notable copper accumulation in the Atp7b−/−kidney is likely due to the compensatory export of copper by ATP7A. This interpretation is supported by the predominant localization of ATP7A at the basolateral membrane of Atp7b−/−cortical tubules. Our results suggest that both Cu-ATPases regulate renal copper, with ATP7A playing a major role in exporting copper via basolateral membranes and protecting renal tissue against copper overload.
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Braiterman, L., L. Nyasae, F. Leves, and A. L. Hubbard. "Critical roles for the COOH terminus of the Cu-ATPase ATP7B in protein stability, trans-Golgi network retention, copper sensing, and retrograde trafficking." American Journal of Physiology-Gastrointestinal and Liver Physiology 301, no. 1 (2011): G69—G81. http://dx.doi.org/10.1152/ajpgi.00038.2011.
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ATP7A and ATP7B are copper-transporting P-type ATPases that are essential to eukaryotic copper homeostasis and must traffic between intracellular compartments to carry out their functions. Previously, we identified a nine-amino acid sequence (F37–E45) in the NH2terminus of ATP7B that is required to retain the protein in the Golgi when copper levels are low and target it apically in polarized hepatic cells when copper levels rise. To understand further the mechanisms regulating the intracellular dynamics of ATP7B, using multiple functional assays, we characterized the protein phenotypes of 10 engineered and Wilson disease-associated mutations in the ATP7B COOH terminus in polarized hepatic cells and fibroblasts. We also examined the behavior of a chimera between ATP7B and ATP7A. Our results clearly demonstrate the importance of the COOH terminus of ATP7B in the protein's copper-responsive apical trafficking. L1373 at the end of transmembrane domain 8 is required for protein stability and Golgi retention in low copper, the trileucine motif (L1454–L1456) is required for retrograde trafficking, and the COOH terminus of ATP7B exhibits a higher sensitivity to copper than does ATP7A. Importantly, our results demonstrating that four Wilson disease-associated missense mutations behaved in a wild-type manner in all our assays, together with current information in the literature, raise the possibility that several may not be disease-causing mutations.
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Materia, Stephanie, Michael A. Cater, Leo W. J. Klomp, Julian F. B. Mercer, and Sharon La Fontaine. "Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B." Journal of Biological Chemistry 286, no. 12 (2011): 10073–83. http://dx.doi.org/10.1074/jbc.m110.190546.
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The copper-transporting P1B-type ATPases (Cu-ATPases) ATP7A and ATP7B are key regulators of physiological copper levels. They function to maintain intracellular copper homeostasis by delivering copper to secretory compartments and by trafficking toward the cell periphery to export excess copper. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and toxicity disorders, Menkes and Wilson diseases, respectively. This report describes the interaction between the Cu-ATPases and clusterin and demonstrates a chaperone-like role for clusterin in facilitating their degradation. Clusterin interacted with both ATP7A and ATP7B in mammalian cells. This interaction increased under conditions of oxidative stress and with mutations in ATP7B that led to its misfolding and mislocalization. A Wilson disease patient mutation (G85V) led to enhanced ATP7B turnover, which was further exacerbated when cells overexpressed clusterin. We demonstrated that clusterin-facilitated degradation of mutant ATP7B is likely to involve the lysosomal pathway. The knockdown and overexpression of clusterin increased and decreased, respectively, the Cu-ATPase-mediated copper export capacity of cells. These results highlight a new role for intracellular clusterin in mediating Cu-ATPase quality control and hence in the normal maintenance of copper homeostasis, and in promoting cell survival in the context of disease. Based on our findings, it is possible that variations in clusterin expression and function could contribute to the variable clinical expression of Menkes and Wilson diseases.
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Dolgova, Nataliya V., Sergiy Nokhrin, Corey H. Yu, Graham N. George, and Oleg Y. Dmitriev. "Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification." Biochemical Journal 454, no. 1 (2013): 147–56. http://dx.doi.org/10.1042/bj20121656.
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Human copper transporters ATP7B (Wilson's disease protein) and ATP7A (Menkes' disease protein) have been implicated in tumour resistance to cisplatin, a widely used anticancer drug. Cisplatin binds to the copper-binding sites in the N-terminal domain of ATP7B, and this binding may be an essential step of cisplatin detoxification involving copper ATPases. In the present study, we demonstrate that cisplatin and a related platinum drug carboplatin produce the same adduct following reaction with MBD2 [metal-binding domain (repeat) 2], where platinum is bound to the side chains of the cysteine residues in the CxxC copper-binding motif. This suggests the same mechanism for detoxification of both drugs by ATP7B. Platinum can also be transferred to MBD2 from copper chaperone Atox1, which was shown previously to bind cisplatin. Binding of the free cisplatin and reaction with the cisplatin-loaded Atox1 produce the same protein-bound platinum intermediate. Transfer of platinum along the copper-transport pathways in the cell may serve as a mechanism of drug delivery to its target in the cell nucleus, and explain tumour-cell resistance to cisplatin associated with the overexpression of copper transporters ATP7B and ATP7A.
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Kelleher, Shannon L., and Bo Lönnerdal. "Mammary gland copper transport is stimulated by prolactin through alterations in Ctr1 and Atp7A localization." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 4 (2006): R1181—R1191. http://dx.doi.org/10.1152/ajpregu.00206.2005.
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Milk copper (Cu) concentration declines and directly reflects the stage of lactation. Three Cu-specific transporters (Ctr1, Atp7A, Atp7B) have been identified in the mammary gland; however, the integrated role they play in milk Cu secretion is not understood. Whereas the regulation of milk composition by the lactogenic hormone prolactin (PRL) has been documented, the specific contribution of PRL to this process is largely unknown. Using the lactating rat as a model, we determined that the normal decline in milk Cu concentration parallels declining Cu availability to the mammary gland and is associated with decreased Atp7B protein levels. Mammary gland Cu transport was highest during early lactation and was stimulated by suckling and hyperprolactinemia, which was associated with Ctr1 and Atp7A localization at the plasma membrane. Using cultured mammary epithelial cells (HC11), we demonstrated that Ctr1 stains in association with intracellular vesicles that partially colocalize with transferrin receptor (recycling endosome marker). Atp7A was primarily colocalized with mannose 6-phosphate receptor (M6PR; late endosome marker), whereas Atp7B was partially colocalized with protein disulfide isomerase (endoplasmic reticulum marker), TGN38 ( trans-Golgi network marker) and M6PR. Prolactin stimulated Cu transport as a result of increased Ctr1 and Atp7A abundance at the plasma membrane. Although the molecular mechanisms responsible for these posttranslational changes are not understood, transient changes in prolactin signaling play a role in the regulation of mammary gland Cu secretion during lactation.
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Inesi, Giuseppe, Rajendra Pilankatta, and Francesco Tadini-Buoninsegni. "Biochemical characterization of P-type copper ATPases." Biochemical Journal 463, no. 2 (2014): 167–76. http://dx.doi.org/10.1042/bj20140741.
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Copper ATPases, in analogy with other members of the P-ATPase superfamily, contain a catalytic headpiece including an aspartate residue reacting with ATP to form a phosphoenzyme intermediate, and transmembrane helices containing cation-binding sites [TMBS (transmembrane metal-binding sites)] for catalytic activation and cation translocation. Following phosphoenzyme formation by utilization of ATP, bound copper undergoes displacement from the TMBS to the lumenal membrane surface, with no H+ exchange. Although PII-type ATPases sustain active transport of alkali/alkali-earth ions (i.e. Na+, Ca2+) against electrochemical gradients across defined membranes, PIB-type ATPases transfer transition metal ions (i.e. Cu+) from delivery to acceptor proteins and, prominently in mammalian cells, undergo trafficking from/to various membrane compartments. A specific component of copper ATPases is the NMBD (N-terminal metal-binding domain), containing up to six copper-binding sites in mammalian (ATP7A and ATP7B) enzymes. Copper occupancy of NMBD sites and interaction with the ATPase headpiece are required for catalytic activation. Furthermore, in the presence of copper, the NMBD allows interaction with protein kinase D, yielding phosphorylation of serine residues, ATP7B trafficking and protection from proteasome degradation. A specific feature of ATP7A is glycosylation and stabilization on plasma membranes. Cisplatin, a platinum-containing anti-cancer drug, binds to copper sites of ATP7A and ATP7B, and undergoes vectorial displacement in analogy with copper.
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Lutsenko, Svetlana, Natalie L. Barnes, Mee Y. Bartee, and Oleg Y. Dmitriev. "Function and Regulation of Human Copper-Transporting ATPases." Physiological Reviews 87, no. 3 (2007): 1011–46. http://dx.doi.org/10.1152/physrev.00004.2006.
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Copper-transporting ATPases (Cu-ATPases) ATP7A and ATP7B are evolutionarily conserved polytopic membrane proteins with essential roles in human physiology. The Cu-ATPases are expressed in most tissues, and their transport activity is crucial for central nervous system development, liver function, connective tissue formation, and many other physiological processes. The loss of ATP7A or ATP7B function is associated with severe metabolic disorders, Menkes disease, and Wilson disease. In cells, the Cu-ATPases maintain intracellular copper concentration by transporting copper from the cytosol across cellular membranes. They also contribute to protein biosynthesis by delivering copper into the lumen of the secretory pathway where metal ion is incorporated into copper-dependent enzymes. The biosynthetic and homeostatic functions of Cu-ATPases are performed in different cell compartments; targeting to these compartments and the functional activity of Cu-ATPase are both regulated by copper. In recent years, significant progress has been made in understanding the structure, function, and regulation of these essential transporters. These studies raised many new questions related to specific physiological roles of Cu-ATPases in various tissues and complex mechanisms that control the Cu-ATPase function. This review summarizes current data on the structural organization and functional properties of ATP7A and ATP7B as well as their localization and functions in various tissues, and discusses the current models of regulated trafficking of human Cu-ATPases.
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CATER, Michael A., John FORBES, Sharon La FONTAINE, Diane COX, and Julian F. B. MERCER. "Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites." Biochemical Journal 380, no. 3 (2004): 805–13. http://dx.doi.org/10.1042/bj20031804.
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The Wilson protein (ATP7B) is a copper-transporting CPx-type ATPase defective in the copper toxicity disorder Wilson disease. In hepatocytes, ATP7B delivers copper to apo-ceruloplasmin and mediates the excretion of excess copper into bile. These distinct functions require the protein to localize at two different subcellular compartments. At the trans-Golgi network, ATP7B transports copper for incorporation into apo-ceruloplasmin. When intracellular copper levels are increased, ATP7B traffics to post-Golgi vesicles in close proximity to the canalicular membrane to facilitate biliary copper excretion. In the present study, we investigated the role of the six N-terminal MBSs (metal-binding sites) in the trafficking process. Using site-directed mutagenesis, we mutated or deleted various combinations of the MBSs and assessed the effect of these changes on the localization and trafficking of ATP7B. Results show that the MBSs required for trafficking are the same as those previously found essential for the copper transport function. Either MBS 5 or MBS 6 alone was sufficient to support the redistribution of ATP7B to vesicular compartments. The first three N-terminal motifs were not required for copper-dependent intracellular trafficking and could not functionally replace sites 4–6 when placed in the same sequence position. Furthermore, the N-terminal region encompassing MBSs 1–5 (amino acids 64–540) was not essential for trafficking, with only one MBS close to the membrane channel, necessary and sufficient to support trafficking. Our findings were similar to those obtained for the closely related ATP7A protein, suggesting similar mechanisms for trafficking between copper-transporting CPx-type ATPases.
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Guo, Y., L. Nyasae, L. T. Braiterman, and A. L. Hubbard. "NH2-terminal signals in ATP7B Cu-ATPase mediate its Cu-dependent anterograde traffic in polarized hepatic cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 289, no. 5 (2005): G904—G916. http://dx.doi.org/10.1152/ajpgi.00262.2005.
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Cu is an essential cofactor of cellular proteins but is toxic in its free state. The hepatic Cu-ATPase ATP7B has two functions in Cu homeostasis: it loads Cu+onto newly synthesized apoceruloplasmin in the secretory pathway, thereby activating the plasma protein; and it participates in the excretion of excess Cu+into the bile. To carry out these two functions, the membrane protein responds to changes in intracellular Cu levels by cycling between the Golgi and apical region. We used polarized hepatic WIF-B cells and high-resolution confocal microscopy to map the itinerary of endogenous and exogenous ATP7B under different Cu conditions. In Cu-depleted cells, ATP7B resided in a post- trans-Golgi network compartment that also contained syntaxin 6, whereas in Cu-loaded cells, the protein relocated to unique vesicles very near to the apical plasma membrane as well as the membrane itself. To determine the role of ATP7B's cytoplasmic NH2terminus in regulating its intracellular movements, we generated seven mutations/deletions in this large [∼650 amino acid (AA)] domain and analyzed the Cu-dependent behavior of the mutant ATP7B proteins in WIF-B cells. Truncation of the ATP7B NH2terminus up to the fifth copper-binding domain (CBD5) yielded an active ATPase that was insensitive to cellular Cu levels and constitutively trafficked to the opposite (basolateral) plasma membrane domain. Fusion of the NH2-terminal 63 AA of ATP7B to the truncated protein restored both its Cu responsiveness and correct intracellular targeting. These results indicate that important targeting information is contained in this relatively short sequence, which is absent from the related CuATPase, ATP7A.
10
Petruzzelli, Raffaella, and Roman S. Polishchuk. "Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs." Cells 8, no. 9 (2019): 1080. http://dx.doi.org/10.3390/cells8091080.
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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.
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Bauerly, Kathryn A., Shannon L. Kelleher, and Bo Lönnerdal. "Effects of copper supplementation on copper absorption, tissue distribution, and copper transporter expression in an infant rat model." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 5 (2005): G1007—G1014. http://dx.doi.org/10.1152/ajpgi.00210.2004.
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Infants are exposed to variable copper (Cu) intake; Cu in breast milk is low, whereas infant formulas vary in Cu content as well as the water used for their preparation. Little is known about the regulation of Cu absorption during infancy. The objectives of this study were to determine effects of Cu supplementation on Cu absorption and tissue distribution and the expression of Cu transporters in an infant rat model. Suckling rat pups were orally dosed with 0, 10, or 25 μg Cu/day. Intestine and liver were collected at days 10 and 20, and Cu concentration, Cu transporter-1 (Ctr1), Atp7A, Atp7B, and metallothionein (MT) mRNA and protein levels were measured.67Cu absorption was measured at days 10 and 20. Total67Cu absorption decreased, and intestinal67Cu retention increased with increased Cu intake. At day 10, intestine Cu concentration, MT mRNA, and Ctr1 protein levels increased with supplementation, but no changes in Atp7A or Atp7B levels were observed. At day 20, intestine Cu concentration was unaffected by Cu supplementation, but Ctr1 protein and Atp7A mRNA and protein levels were higher than in controls. In liver, Cu level reflected Cu intake at days 10 and 20. There was a significant increase in Ctr1, Atp7B, and MT mRNA expression in liver at both ages with Cu supplementation. In conclusion, the ability of suckling rat pups to tolerate varying amounts of dietary Cu may be due to changes in Cu transporters, facilitated by transcriptional and posttranslational mechanisms. Despite these adaptive changes, Cu supplementation resulted in elevated alanine aminotransferase levels, suggesting a risk of Cu toxicity with supplementation during infancy.
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Linz, Rachel, and Svetlana Lutsenko. "Copper-transporting ATPases ATP7A and ATP7B: cousins, not twins." Journal of Bioenergetics and Biomembranes 39, no. 5-6 (2007): 403–7. http://dx.doi.org/10.1007/s10863-007-9101-2.
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Das, Santanu, Saptarshi Maji, Ruturaj, et al. "Retromer retrieves the Wilson disease protein ATP7B from endolysosomes in a copper-dependent manner." Journal of Cell Science 133, no. 24 (2020): jcs246819. http://dx.doi.org/10.1242/jcs.246819.
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ABSTRACTThe Wilson disease protein, ATP7B maintains copper (herein referring to the Cu+ ion) homeostasis in the liver. ATP7B traffics from trans-Golgi network to endolysosomes to export excess copper. Regulation of ATP7B trafficking to and from endolysosomes is not well understood. We investigated the fate of ATP7B after copper export. At high copper levels, ATP7B traffics primarily to acidic, active hydrolase (cathepsin-B)-positive endolysosomes and, upon subsequent copper chelation, returns to the trans-Golgi network (TGN). At high copper, ATP7B colocalizes with endolysosomal markers and with a core member of retromer complex, VPS35. Knocking down VPS35 did not abrogate the copper export function of ATP7B or its copper-responsive anterograde trafficking to vesicles; rather upon subsequent copper chelation, ATP7B failed to relocalize to the TGN, which was rescued by overexpressing wild-type VPS35. Overexpressing mutants of the retromer complex-associated proteins Rab7A and COMMD1 yielded a similar non-recycling phenotype of ATP7B. At high copper, VPS35 and ATP7B are juxtaposed on the same endolysosome and form a large complex that is stabilized by in vivo photoamino acid labeling and UV-crosslinking. We demonstrate that retromer regulates endolysosome to TGN trafficking of copper transporter ATP7B in a manner that is dependent upon intracellular copper.
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Wooton-Kee, Clavia Ruth, Matthew Robertson, Ying Zhou, et al. "Metabolic dysregulation in the Atp7b−/− Wilson’s disease mouse model." Proceedings of the National Academy of Sciences 117, no. 4 (2020): 2076–83. http://dx.doi.org/10.1073/pnas.1914267117.
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Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b−/− mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors decreased in Atp7b−/− mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b−/− mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography–mass spectrometry and correlated with transcriptomic data. Atp7b−/− mice fed a chow diet presented with blunted body-weight gain over time, had lower fat mass, and were more glucose tolerant than wild type (WT) littermate controls. On the Western diet, Atp7b−/− mice exhibited reduced body weight, adiposity, and hepatic steatosis compared with WT controls. Atp7b−/− mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b−/− mice exhibited hypoglycemia after administration of insulin due to an impaired glucose counterregulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b−/− mice, including increases in glycolytic intermediates and components of the tricarboxylic acid cycle. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b−/− mice relative to WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity as well as with impaired fasting glucose production in Atp7b−/− mice.
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Pantoom, Supansa, Adam Pomorski, Katharina Huth, et al. "Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy." Cells 10, no. 11 (2021): 3118. http://dx.doi.org/10.3390/cells10113118.
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Macroautophagy/autophagy plays an important role in cellular copper clearance. The means by which the copper metabolism and autophagy pathways interact mechanistically is vastly unexplored. Dysfunctional ATP7B, a copper-transporting ATPase, is involved in the development of monogenic Wilson disease, a disorder characterized by disturbed copper transport. Using in silico prediction, we found that ATP7B contains a number of potential binding sites for LC3, a central protein in the autophagy pathway, the so-called LC3 interaction regions (LIRs). The conserved LIR3, located at the C-terminal end of ATP7B, was found to directly interact with LC3B in vitro. Replacing the two conserved hydrophobic residues W1452 and L1455 of LIR3 significantly reduced interaction. Furthermore, autophagy was induced in normal human hepatocellular carcinoma cells (HepG2) leading to enhanced colocalization of ATP7B and LC3B on the autophagosome membranes. By contrast, HepG2 cells deficient of ATP7B (HepG2 ATP7B−/−) showed autophagy deficiency at elevated copper condition. This phenotype was complemented by heterologous ATP7B expression. These findings suggest a cooperative role of ATP7B and LC3B in autophagy-mediated copper clearance.
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Gourdon, Pontus, Oleg Sitsel, Jesper Lykkegaard Karlsen, Lisbeth Birk Møller, and Poul Nissen. "Structural models of the human copper P-type ATPases ATP7A and ATP7B." Biological Chemistry 393, no. 4 (2012): 205–16. http://dx.doi.org/10.1515/hsz-2011-0249.
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Abstract The human copper exporters ATP7A and ATP7B contain domains common to all P-type ATPases as well as class-specific features such as six sequential heavy-metal binding domains (HMBD1–HMBD6) and a type-specific constellation of transmembrane helices. Despite the medical significance of ATP7A and ATP7B related to Menkes and Wilson diseases, respectively, structural information has only been available for isolated, soluble domains. Here we present homology models based on the existing structures of soluble domains and the recently determined structure of the homologous LpCopA from the bacterium Legionella pneumophila. The models and sequence analyses show that the domains and residues involved in the catalytic phosphorylation events and copper transfer are highly conserved. In addition, there are only minor differences in the core structures of the two human proteins and the bacterial template, allowing protein-specific properties to be addressed. Furthermore, the mapping of known disease-causing missense mutations indicates that among the heavy-metal binding domains, HMBD5 and HMBD6 are the most crucial for function, thus mimicking the single or dual HMBDs found in most copper-specific P-type ATPases. We propose a structural arrangement of the HMBDs and how they may interact with the core of the proteins to achieve autoinhibition.
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Katagiri, Hiroshi, Kentaro Nakayama, Mohammed Tanjimur Rahman, et al. "Is ATP7B a Predictive Marker in Patients With Ovarian Carcinoma Treated With Platinum-Taxane Combination Chemotherapy?" International Journal of Gynecologic Cancer 23, no. 1 (2013): 60–64. http://dx.doi.org/10.1097/igc.0b013e318275afef.
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ObjectiveThis study examined the prognostic significance of copper-transporting P-type adenosine triphosphatase (ATP7B) expression in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy.MethodsExpression of ATP7B in ovarian carcinoma was assessed by immunohistochemistry and clinical data collected by retrospective review of medical charts.ResultsOverexpression of ATP7B was identified in 25 (29.1%) of 86 ovarian carcinomas. The frequency of ATP7B expression in clear cell carcinomas was significantly higher than that in serous high-grade carcinomas (P< 0.05). We observed no statistically significant correlations between high ATP7B protein expression and either disease-free survival (P= 0.722) or overall survival (P= 0.389).ConclusionsOur study is the first to demonstrate a lack of statistically significant differences between ATP7B positive and negative cases with respect to prognosis of patients with ovarian carcinoma treated with a platinum-taxane combination regimen. However, that ATP7B expression in clear cell carcinomas was significantly higher than that in serous carcinomas may partially explain the difference in chemotherapeutic response and prognosis between patients with these 2 types of carcinomas.
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Petruzzelli, Raffaella, Marta Mariniello, Rossella De Cegli, et al. "TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells." Cells 11, no. 2 (2022): 219. http://dx.doi.org/10.3390/cells11020219.
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ATP7B is a hepato-specific Golgi-located ATPase, which plays a key role in the regulation of copper (Cu) homeostasis and signaling. In response to elevated Cu levels, ATP7B traffics from the Golgi to endo-lysosomal structures, where it sequesters excess copper and further promotes its excretion to the bile at the apical surface of hepatocytes. In addition to liver, high ATP7B expression has been reported in tumors with elevated resistance to platinum (Pt)-based chemotherapy. Chemoresistance to Pt drugs represents the current major obstacle for the treatment of large cohorts of cancer patients. Although the mechanisms underlying Pt-tolerance are still ambiguous, accumulating evidence suggests that lysosomal sequestration of Pt drugs by ion transporters (including ATP7B) might significantly contribute to drug resistance development. In this context, signaling mechanisms regulating the expression of transporters such as ATP7B are of great importance. Considering this notion, we investigated whether ATP7B expression in Pt-resistant cells might be driven by transcription factor EB (TFEB), a master regulator of lysosomal gene transcription. Using resistant ovarian cancer IGROV-CP20 cells, we found that TFEB directly binds to the predicted coordinated lysosomal expression and regulation (CLEAR) sites in the proximal promoter and first intron region of ATP7B upon Pt exposure. This binding accelerates transcription of luciferase reporters containing ATP7B CLEAR regions, while suppression of TFEB inhibits ATP7B expression and stimulates cisplatin toxicity in resistant cells. Thus, these data have uncovered a Pt-dependent transcriptional mechanism that contributes to cancer chemoresistance and might be further explored for therapeutic purposes.
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Dmitriev, Oleg Y. "Mechanism of tumor resistance to cisplatin mediated by the copper transporter ATP7BThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process." Biochemistry and Cell Biology 89, no. 2 (2011): 138–47. http://dx.doi.org/10.1139/o10-150.
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The Wilson disease protein (ATP7B) is a copper-transporting ATPase that is responsible for regulating copper homeostasis in human tissues. ATP7B is associated with cancer resistance to cisplatin, one of the most widely used anticancer drugs. This minireview discusses the possible mechanisms of tumor resistance to cisplatin mediated by ATP7B. Cisplatin binds to the N-terminal cytosolic domain of ATP7B, which contains multiple copper-binding sites. Active platinum efflux catalyzed by ATP7B is unlikely to significantly contribute to cisplatin resistance in vivo. Transient platinum sequestration in the metal-binding domain followed by transfer to an acceptor protein or a low molecular weight compound is proposed as an alternative mechanism of cisplatin detoxification in the cell.
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Jain, Shweta, Ginny G. Farías, and Juan S. Bonifacino. "Polarized sorting of the copper transporter ATP7B in neurons mediated by recognition of a dileucine signal by AP-1." Molecular Biology of the Cell 26, no. 2 (2015): 218–28. http://dx.doi.org/10.1091/mbc.e14-07-1177.
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Neurons are highly polarized cells having distinct somatodendritic and axonal domains. Here we report that polarized sorting of the Cu2+ transporter ATP7B and the vesicle-SNARE VAMP4 to the somatodendritic domain of rat hippocampal neurons is mediated by recognition of dileucine-based signals in the cytosolic domains of the proteins by the σ1 subunit of the clathrin adaptor AP-1. Under basal Cu2+ conditions, ATP7B was localized to the trans-Golgi network (TGN) and the plasma membrane of the soma and dendrites but not the axon. Mutation of a dileucine-based signal in ATP7B or overexpression of a dominant-negative σ1 mutant resulted in nonpolarized distribution of ATP7B between the somatodendritic and axonal domains. Furthermore, addition of high Cu2+ concentrations, previously shown to reduce ATP7B incorporation into AP-1–containing clathrin-coated vesicles, caused loss of TGN localization and somatodendritic polarity of ATP7B. These findings support the notion of AP-1 as an effector of polarized sorting in neurons and suggest that altered polarity of ATP7B in polarized cell types might contribute to abnormal copper metabolism in the MEDNIK syndrome, a neurocutaneous disorder caused by mutations in the σ1A subunit isoform of AP-1.
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Mortazavi, Mojtaba, Abdolrazagh Barzegar, Abdorrasoul Malekpour, Mohammad Ghorbani, Saeid Gholamzadeh, and Younes Ghasemi. "In Silico Evaluation of the ATP7B Protein: Insights from the Role of Rare Codon Clusters and Mutations that Affect Protein Structure and Function." Current Proteomics 17, no. 3 (2020): 213–26. http://dx.doi.org/10.2174/1570164617666190919114545.
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Background: Wilson’s disease is a rare autosomal recessive genetic disorder of copper metabolism, which is characterized by hepatic and neurological disease. ATP7B encodes a transmembrane protein ATPase (ATP7B), which functions as a copper-dependent P-type ATPase. The mutations in the gene ATP7B (on chromosome 13) lead to Wilson’s disease and is highly expressed in the liver, kidney, and placenta. Consequently, this enzyme was considered a special topic in clinical and biotechnological research. For in silico analysis, the 3D molecular modeling of this enzyme was conducted in the I-TASSER web server. Methods: For a better evaluation, the important characteristics of this enzyme such as the rare codons of the ATP7B gene were evaluated by online software, including a rare codon calculator (RCC), ATGme, LaTcOm, and Sherlocc program. Additionally, the multiple sequence alignment of this enzyme was studied. Finally, for evaluation of the effects of rare codons, the 3D structure of ATP7B was modeled in the Swiss Model and I-TASSER web server. Results: The results showed that the ATP7B gene has 35 single rare codons for Arg. Additionally, RCC detected two rare codons for Leu, 13 single rare codons for Ile and 28 rare codons for the Pro. ATP7B gene analysis in minmax and sliding_window algorithm resulted in the identification of 16 and 17 rare codon clusters, respectively, indicating the different features of these algorithms in the detection of RCCs. Analyzing the 3D model of ATP7B protein showed that Arg816 residue constitutes hydrogen bonds with Glu810 and Glu816. Mutation of this residue to Ser816 cause these hydrogen bonds not to be formed and may interfere in the proper folding of ATP7B protein. Furthermore, the side chain of Arg1228 does not form any bond with other residues. By mutation of Arg1228 to Thr1228, a new hydrogen bond is formed with the side chain of Arg1228. The addition and deletion of hydrogen bonds alter the proper folding of ATP7B protein and interfere with the proper function of the ATP7B position. On the other hand, His1069 forms the hydrogen bonds with the His880 and this hydrogen bond adhere two regions of the protein together, which is critical in the final structural folding of ATP7B protein. Conclusion: Previous studies show that synonymous and silent mutations have been linked to numerous diseases. Given the importance of synonymous and silent mutations in diseases, the aim of this study was to investigate the rare codons (synonymous codons) in the structure of ATP7B enzyme. By these analyses, a new understanding was developed and our findings can further be used in some fields of the clinical and industrial biotechnology.
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Singla, Amika, Qing Chen, Kohei Suzuki, et al. "Regulation of murine copper homeostasis by members of the COMMD protein family." Disease Models & Mechanisms 14, no. 1 (2020): dmm045963. http://dx.doi.org/10.1242/dmm.045963.
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ABSTRACTCopper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominantly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be recycled actively between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and in mice with liver-specific Commd1 deficiency, recapitulating aspects of this phenotype. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused destabilization of the entire CCC complex and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.
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Braiterman, Lelita, Lydia Nyasae, Yan Guo, Rodrigo Bustos, Svetlana Lutsenko, and Ann Hubbard. "Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 2 (2009): G433—G444. http://dx.doi.org/10.1152/ajpgi.90489.2008.
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ATP7B is a copper-transporting P-type ATPase present predominantly in liver. In basal copper, hepatic ATP7B is in a post-trans-Golgi network (TGN) compartment where it loads cytoplasmic Cu(I) onto newly synthesized ceruloplasmin. When copper levels rise, the protein redistributes via unique vesicles to the apical periphery where it exports intracellular Cu(I) into bile. We want to understand the mechanisms regulating the copper-sensitive trafficking of ATP7B. Earlier, our laboratory reported the presence of apical targeting/TGN retention information within residues 1–63 of human ATP7B; deletion of these residues resulted in a mutant protein that was not efficiently retained in the post-TGN in low copper and constitutively trafficked to the basolateral membrane of polarized, hepatic WIF-B cells with and without copper ( 13 ). In this study, we used mutagenesis and adenovirus infection of WIF-B cells followed by confocal immunofluorescence microscopy analysis to identify the precise retention/targeting sequences in the context of full-length ATP7B. We also analyzed the expression of selected mutants in livers of copper-deficient and -loaded mice. Our combined results clearly demonstrate that nine amino acids, F37AFDNVGYE45, comprise an essential apical targeting determinant for ATP7B in elevated copper and participate in the TGN retention of the protein under low-copper conditions. The signal is novel, does not require phosphorylation, and is highly conserved in ∼24 species of ATP7B. Furthermore, N41S, which is part of the signal we identified, is the first and only Wilson disease-causing missense mutation in residues 1–63 of ATP7B. Expression of N41S-ATP7B in WIF-B cells severely disabled the targeting and retention of the protein. We present a working model of how this physiologically relevant signal might work.
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Cater, Michael A., Sharon La fontaine, and Julian F. B. Mercer. "Copper binding to the N-terminal metal-binding sites or the CPC motif is not essential for copper-induced trafficking of the human Wilson protein (ATP7B)." Biochemical Journal 401, no. 1 (2006): 143–53. http://dx.doi.org/10.1042/bj20061055.
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The Wilson protein (ATP7B) is a copper-translocating P-type ATPase that mediates the excretion of excess copper from hep-atocytes into bile. Excess copper causes the protein to traffic from the TGN (trans-Golgi network) to subapical vesicles. Using site-directed mutagenesis, mutations known or predicted to abrogate catalytic activity (copper translocation) were introduced into ATP7B and the effect of these mutations on the intracellular traf-ficking of the protein was investigated. Mutation of the critical aspartic acid residue in the phosphorylation domain (DKTGTIT) blocked copper-induced redistribution of ATP7B from the TGN, whereas mutation of the phosphatase domain [TGE (Thr-Gly-Glu)] trapped ATP7B at cytosolic vesicular compartments. Our findings demonstrate that ATP7B trafficking is regulated with its copper-translocation cycle, with cytosolic vesicular localization associated with the acyl-phosphate intermediate. In addition, mut-ation of the six N-terminal metal-binding sites and/or the trans-membrane CPC (Cys-Pro-Cys) motif did not suppress the consti-tutive vesicular localization of the ATP7B phosphatase domain mutant. These results suggested that copper co-ordination by these sites is not essential for trafficking. Importantly, copper-chelation studies with these mutants clearly demonstrated a requirement for copper in ATP7B trafficking, suggesting the presence of an additional copper-binding site(s) within the protein. The results presented in this report significantly advance our understanding of the regulatory mechanism that links copper-translocation activity with copper-induced intracellular trafficking of ATP7B, which is central to hepatic and hence systemic copper homoeostasis.
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Terada, Kunihiko, Michael L. Schilsky, Naoyuki Miura, and Toshihiro Sugiyama. "ATP7B (WND) protein." International Journal of Biochemistry & Cell Biology 30, no. 10 (1998): 1063–67. http://dx.doi.org/10.1016/s1357-2725(98)00073-9.
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Muchenditsi, Abigael, Haojun Yang, James P. Hamilton, et al. "Targeted inactivation of copper transporter Atp7b in hepatocytes causes liver steatosis and obesity in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 313, no. 1 (2017): G39—G49. http://dx.doi.org/10.1152/ajpgi.00312.2016.
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Copper-transporting ATPase 2 (ATP7B) is essential for mammalian copper homeostasis. Mutations in ATP7B result in copper accumulation, especially in the liver, and cause Wilson disease (WD). The major role of hepatocytes in WD pathology is firmly established. It is less certain whether the excess Cu in hepatocytes is solely responsible for development of WD. To address this issue, we generated a mouse strain for Cre-mediated deletion of Atp7b and inactivated Atp7b selectively in hepatocytes. Atp7bΔHep mice accumulate copper in the liver, have elevated urinary copper, and lack holoceruloplasmin but show no liver disease for up to 30 wk. Liver inflammation is muted and markedly delayed compared with the age-matched Atp7b−/− null mice, which show a strong type1 inflammatory response. Expression of metallothioneins is higher in Atp7bΔHep livers than in Atp7b−/− mice, suggesting better sequestration of excess copper. Characterization of purified cell populations also revealed that nonparenchymal cells in Atp7bΔHep liver maintain Atp7b expression, have normal copper balance, and remain largely quiescent. The lack of inflammation unmasked metabolic consequences of copper misbalance in hepatocytes. Atp7bΔHep animals weigh more than controls and have higher levels of liver triglycerides and 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. By 45 wk, all animals develop liver steatosis on a regular diet. Thus copper misbalance in hepatocytes dysregulates lipid metabolism, whereas development of inflammatory response in WD may depend on copper status of nonparenchymal cells. The implications of these findings for the cell-targeting WD therapies are discussed. NEW & NOTEWORTHY Targeted inactivation of copper-transporting ATPase 2 (Atp7b) in hepatocytes causes steatosis in the absence of inflammation.
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Moore, Steven D. P., and Diane W. Cox. "Expression in Mouse Kidney of Membrane Copper Transporters Atp7a and Atp7b." Nephron 92, no. 3 (2002): 629–34. http://dx.doi.org/10.1159/000064075.
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Tadini-Buoninsegni, Francesco, and Serena Smeazzetto. "Mechanisms of charge transfer in human copper ATPases ATP7A and ATP7B." IUBMB Life 69, no. 4 (2017): 218–25. http://dx.doi.org/10.1002/iub.1603.
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La Fontaine, Sharon, M. Leigh Ackland, and Julian F. B. Mercer. "Mammalian copper-transporting P-type ATPases, ATP7A and ATP7B: Emerging roles." International Journal of Biochemistry & Cell Biology 42, no. 2 (2010): 206–9. http://dx.doi.org/10.1016/j.biocel.2009.11.007.
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Asada, Hajime, James K. Chambers, Mari Kojima, et al. "Variations in ATP7B in cats with primary copper-associated hepatopathy." Journal of Feline Medicine and Surgery 22, no. 8 (2019): 753–59. http://dx.doi.org/10.1177/1098612x19884763.
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Objectives Primary copper-associated hepatopathy (PCH) has been reported in young cats. Although our group recently reported a young cat with PCH harbouring single-nucleotide variations in ATP7B, limited information is available regarding its association with the pathogenesis of feline PCH. The objective of this study was to investigate the prevalence of ATP7B variations in cats with PCH. Methods Rhodanine staining was performed to detect hepatic copper accumulation (HCA) in intraoperative liver tissue specimens from 54 cats. In cats with HCA, variations in ATP7B and COMMD1 and serum ceruloplasmin activity were analysed. Results Based on age, liver histopathological findings and hepatic distribution of accumulated copper, PCH was suspected in 4/54 cats. Sequence analysis of ATP7B and COMMD1 revealed single-nucleotide variations in ATP7B in 3/4 cats with PCH. Among the cats with PCH, one showed remarkably low serum ceruloplasmin activity, while the other three did not. Conclusions and relevance The results of this study suggest that some cats with PCH harbour single-nucleotide variations in ATP7B, suggesting that feline PCH is an equivalent disorder to human Wilson’s disease. This study provides basic evidence facilitating further studies of the pathophysiology and treatment of feline PCH.
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Tillquist, Nicole M., Meghan P. Thorndyke, Tyler A. Thomas, Stephen J. Coleman, and Terry E. Engle. "PSVII-21 The impact of cell culture and copper dose on copper trafficking genes in bovine liver." Journal of Animal Science 98, Supplement_4 (2020): 307–8. http://dx.doi.org/10.1093/jas/skaa278.549.
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Abstract The objective of the current experiment was to investigate the influence of Cu dose on the relative abundance of Cu trafficking genes in cultured bovine hepatocytes. A liver sample was obtained immediately post-mortem from one healthy Angus steer. Hepatocytes were isolated, counted, and seeded at equal density into 15 separate wells, and incubated for 1 hour in culture media containing: 0.0, 0.10, 1.0, 10.0, or 100 mg Cu/L (3 replicates per Cu dose). Following incubation, cells were collected and total RNA was isolated. Quantitative RT-PCR was used to determine the abundance of transcripts for proteins involved in Cu homeostasis. The identified targets were: ALDH2, APOA1, ATOX1, ATP7A, ATP7B, BHMT, BLVRB, CA2, CCS, COX17, CTR1, ELN, GAPDH, GLUD1, GSS, LOXL1, PDIA3, SOD1, SOD3. β-Actin (ACTB) served as the endogenous control. Significant linear responses existed for ALDH2 (P &lt; 0.001), ATOX1 (P &lt; 0.01), PDIA3 (P &lt; 0.05). As Cu dose increased, the relative abundance of ALDH2 increased, and ATOX1 and PDIA3 decreased. Significant quadratic responses existed for ATP7B (P &lt; 0.001), COX17 (P &lt; 0.05), and SOD1 (P &lt; 0.05). The relative abundance of COX17 was lesser at 0.1 and 1.0 mg Cu/L when compared to 0.0, 10, and 100 mg Cu/L. Transcript abundance for ATP7B and SOD1 was lower at 0, 1, and 100 mg Cu/L when compared to 0.1 and 10 mg Cu/L. These data indicate that certain transcripts are differentially expressed in cultured bovine hepatocytes in response to increasing Cu dose.
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Miyayama, Takamitsu, Daisuke Hiraoka, Fumika Kawaji, Emi Nakamura, Noriyuki Suzuki, and Yasumitsu Ogra. "Roles of COMM-domain-containing 1 in stability and recruitment of the copper-transporting ATPase in a mouse hepatoma cell line." Biochemical Journal 429, no. 1 (2010): 53–61. http://dx.doi.org/10.1042/bj20100223.
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A novel function of COMMD1 {COMM [copper metabolism MURR1 (mouse U2af1-rs1 region 1)]-domain-containing 1}, a protein relevant to canine copper toxicosis, was examined in the mouse hepatoma cell line Hepa 1-6 with multi-disciplinary techniques consisting of molecular and cellular biological techniques, speciation and elemental imaging. To clarify the function of COMMD1, COMMD1-knockdown was accomplished by introducing siRNA (small interfering RNA) into the cells. Although COMMD1-knockdown did not affect copper incorporation, it inhibited copper excretion, resulting in copper accumulation, which predominantly existed in the form bound to MT (metallothionein). It is known that the liver copper transporter Atp7b (ATP-dependent copper transporter 7β), localizes on the trans-Golgi network membrane under basal copper conditions and translocates to cytoplasmic vesicles to excrete copper when its concentration exceeds a certain threshold, with the vesicles dispersing in the periphery of the cell. COMMD1-knockdown reduced the expression of Atp7b, and abolished the relocation of Atp7b back from the periphery to the trans-Golgi network membrane when the copper concentration was reduced by treatment with a Cu(I) chelator. The same phenomena were observed during COMMD1-knockdown when another Atp7b substrate, cis-diamminedichloroplatinum, and its sequestrator, glutathione ethylester, were applied. These results suggest that COMMD1 maintains the amount of Atp7b and facilitates recruitment of Atp7b from cytoplasmic vesicles to the trans-Golgi network membrane, i.e. COMMD1 is required to shuttle Atp7b when the intracellular copper level returns below the threshold.
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Mariniello, Marta, Raffaella Petruzzelli, Luca G. Wanderlingh, et al. "Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin." Cancers 12, no. 3 (2020): 608. http://dx.doi.org/10.3390/cancers12030608.
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Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.
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McCann, Courtney J., Samuel Jayakanthan, Mariacristina Siotto, et al. "Correction: Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein." Metallomics 11, no. 8 (2019): 1441. http://dx.doi.org/10.1039/c9mt90028d.
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Vyas, Avani, Umamaheswar Duvvuri, and Kirill Kiselyov. "Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity." Biochemical Journal 476, no. 24 (2019): 3705–19. http://dx.doi.org/10.1042/bcj20190591.
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Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.
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MICHALCZYK, Agnes A., Jennifer RIEGER, Katrina J. ALLEN, Julian F. B. MERCER, and M. Leigh ACKLAND. "Defective localization of the Wilson disease protein (ATP7B) in the mammary gland of the toxic milk mouse and the effects of copper supplementation." Biochemical Journal 352, no. 2 (2000): 565–71. http://dx.doi.org/10.1042/bj3520565.
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Toxic milk (tx) is a copper disorder of mice that causes a hepatic accumulation of copper similar to that seen in patients with Wilson disease. Both disorders are caused by a defect in the ATP7B copper-transporting ATPase. A feature of the tx phenotype is the production of copper-deficient milk by lactating dams homozygous for the tx mutation; the milk is lethal to the pups. It has not been determined whether the production of copper-deficient milk is a direct consequence of impaired expression of ATP7B protein in the mammary gland. With the use of immunohistochemistry, our study demonstrated that the ATP7B protein was mislocalized in the lactating tx mouse mammary gland, which would explain the inability of the tx mouse to secrete normal amounts of copper in milk. Confocal microscopy analysis showed that, in the lactating tx mammary gland, ATP7B was predominantly perinuclear in comparison with the diffuse, cytoplasmic localization of ATP7B in the lactating normal mammary gland. Lactating tx mice showed impaired delivery of copper from the mammary gland to the milk and this was not ameliorated by dietary copper supplementation. In contrast, the normal mouse mammary gland responded to increased dietary copper by increasing the amount of copper in milk. A change in the distribution of the ATP7B protein from perinuclear in the non-lactating gland to a diffuse, cytoplasmic localization in the lactating gland of the normal (DL) mouse suggests that the relocalization of APT7B is a physiological process that accompanies lactation. We conclude that the impaired copper transport from the mammary gland into milk in lactating tx mice is related to the mislocalization of ATP7B.
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Dolgova, Nataliya V., Doug Olson, Svetlana Lutsenko, and Oleg Y. Dmitriev. "The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin." Biochemical Journal 419, no. 1 (2009): 51–59. http://dx.doi.org/10.1042/bj20081359.
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Wilson disease ATPase (ATP7B) has been implicated in the resistance of cancer cells to cisplatin. Using a simple in vivo assay in bacterial culture, in the present study we demonstrate that ATP7B can confer resistance to cisplatin by sequestering the drug in its N-terminal metal-binding domain without active drug extrusion from the cell. Expression of a protein fragment containing four N-terminal MBRs (metal-binding repeats) of ATP7B (MBR1–4) protects cells from the toxic effects of cisplatin. One MBR1–4 molecule binds up to three cisplatin molecules at the copper-binding sites in the MBRs. The findings of the present study suggest that suppressing enzymatic activity of ATP7B may not be an effective way of combating cisplatin resistance. Rather, the efforts should be directed at preventing cisplatin binding to the protein.
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Tadini-Buoninsegni, Francesco, Gianluca Bartolommei, Maria Rosa Moncelli, et al. "Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B." Angewandte Chemie International Edition 53, no. 5 (2013): 1297–301. http://dx.doi.org/10.1002/anie.201307718.
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Tadini-Buoninsegni, Francesco, Gianluca Bartolommei, Maria Rosa Moncelli, et al. "Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B." Angewandte Chemie 126, no. 5 (2013): 1321–25. http://dx.doi.org/10.1002/ange.201307718.
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La Fontaine, Sharon, and Julian F. B. Mercer. "Trafficking of the copper-ATPases, ATP7A and ATP7B: Role in copper homeostasis." Archives of Biochemistry and Biophysics 463, no. 2 (2007): 149–67. http://dx.doi.org/10.1016/j.abb.2007.04.021.
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Lacombe, Maud, Michel Jaquinod, Lucid Belmudes, et al. "Comprehensive and comparative exploration of the Atp7b−/− mouse plasma proteome." Metallomics 12, no. 2 (2020): 249–58. http://dx.doi.org/10.1039/c9mt00225a.
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Wilson's disease (WD) is a rare genetic disease caused by mutations in the ATP7B gene. In this study, we used MS-based proteomics to explore the plasma proteome of the Atp7b<sup>−/−</sup> mouse, a genetic and phenotypic model for WD.
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Lutsenko, Svetlana. "Atp7b −/− mice as a model for studies of Wilson's disease." Biochemical Society Transactions 36, no. 6 (2008): 1233–38. http://dx.doi.org/10.1042/bst0361233.
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Wilson's disease is a severe human disorder of copper homoeostasis. The disease is associated with various mutations in the ATP7B gene that encodes a copper-transporting ATPase, and a massive accumulation of copper in the liver and several other tissues. The most frequent disease manifestations include a wide spectrum of liver pathologies as well as neurological and psychiatric abnormalities. A combination of copper chelators and zinc therapy has been used to prevent disease progression; however, accurate and timely diagnosis of the disease remains challenging. Similarly, side effects of treatments are common. To understand better the biochemical and cellular basis of Wilson's disease, several animal models have been developed. This review focuses on genetically engineered Atp7b−/− mice and describes the properties of these knockout animals, insights into the disease progression generated using Atp7b−/− mice, as well as advantages and limitations of Atp7b−/− mice as an experimental model for Wilson's disease.
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Sharma, Yogeshwar, Jinghua Liu, Kathleen E. Kristian, Antonia Follenzi, and Sanjeev Gupta. "In Atp7b−/− Mice Modeling Wilson’s Disease Liver Repopulation With Bone Marrow-Derived Myofibroblasts or Inflammatory Cells and Not Hepatocytes Is Deleterious." Gene Expression 19, no. 1 (2019): 15–24. http://dx.doi.org/10.3727/105221618x15320123457380.
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In Wilson’s disease, Atp7b mutations impair copper excretion with liver or brain damage. Healthy transplanted hepatocytes repopulate the liver, excrete copper, and reverse hepatic damage in animal models of Wilson’s disease. In Fah−/− mice with tyrosinemia and α-1 antitrypsin mutant mice, liver disease is resolved by expansions of healthy hepatocytes derived from transplanted healthy bone marrow stem cells. This potential of stem cells has not been defined for Wilson’s disease. In diseased Atp7b−/− mice, we reconstituted bone marrow with donor cells expressing green fluorescent protein reporter from healthy transgenic mice. Mature hepatocytes originating from donor bone marrow were identified by immunostaining for green fluorescence protein and bile canalicular marker, dipeptidylpeptidase-4. Mesenchymal and inflammatory cell markers were used for other cells from donor bone marrow cells. Gene expression, liver tests, and tissues were analyzed for outcomes in Atp7b−/− mice. After bone marrow transplantation in Atp7b−/− mice, donor-derived hepatocytes containing bile canaliculi appeared within weeks. Despite this maturity, donor-derived hepatocytes neither divided nor expanded. The liver of Atp7b−/− mice was not repopulated by donor-derived hepatocytes: Atp7b mRNA remained undetectable; liver tests, copper content, and fibrosis actually worsened. Restriction of proliferation in hepatocytes accompanied oxidative DNA damage. By contrast, donor-derived mesenchymal and inflammatory cells extensively proliferated. These contributed to fibrogenesis through greater expression of inflammatory cytokines. In Wilson’s disease, donor bone marrow-derived cells underwent different fates: hepatocytes failed to proliferate; inflammatory cells proliferated to worsen disease outcomes. This will help guide stem cell therapies for conditions with proinflammatory or profibrogenic microenvironments.
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Montes, Sergio, Susana Rivera-Mancia, Araceli Diaz-Ruiz, Luis Tristan-Lopez, and Camilo Rios. "Copper and Copper Proteins in Parkinson’s Disease." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/147251.
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Copper is a transition metal that has been linked to pathological and beneficial effects in neurodegenerative diseases. In Parkinson’s disease, free copper is related to increased oxidative stress, alpha-synuclein oligomerization, and Lewy body formation. Decreased copper along with increased iron has been found insubstantia nigraand caudate nucleus of Parkinson’s disease patients. Copper influences iron content in the brain through ferroxidase ceruloplasmin activity; therefore decreased protein-bound copper in brain may enhance iron accumulation and the associated oxidative stress. The function of other copper-binding proteins such as Cu/Zn-SOD and metallothioneins is also beneficial to prevent neurodegeneration. Copper may regulate neurotransmission since it is released after neuronal stimulus and the metal is able to modulate the function of NMDA and GABA A receptors. Some of the proteins involved in copper transport are the transporters CTR1, ATP7A, and ATP7B and the chaperone ATOX1. There is limited information about the role of those biomolecules in the pathophysiology of Parkinson’s disease; for instance, it is known that CTR1 is decreased insubstantia nigra pars compactain Parkinson’s disease and that a mutation in ATP7B could be associated with Parkinson’s disease. Regarding copper-related therapies, copper supplementation can represent a plausible alternative, while copper chelation may even aggravate the pathology.
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Concilli, Mafalda, Raffaella Petruzzelli, Silvia Parisi, et al. "Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B." Proceedings of the National Academy of Sciences 117, no. 51 (2020): 32453–63. http://dx.doi.org/10.1073/pnas.2006648117.
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Pathogenic mutations in the copper transporterATP7Bhave been hypothesized to affect its protein interaction landscape contributing to loss of function and, thereby, to hepatic copper toxicosis in Wilson disease. Although targeting mutant interactomes was proposed as a therapeutic strategy, druggable interactors for rescue of ATP7B mutants remain elusive. Using proteomics, we found that the frequent H1069Q substitution promotes ATP7B interaction with HSP70, thus accelerating endoplasmic reticulum (ER) degradation of the mutant protein and consequent copper accumulation in hepatic cells. This prompted us to use an HSP70 inhibitor as bait in a bioinformatics search for structurally similar Food and Drug Administration-approved drugs. Among the hits, domperidone emerged as an effective corrector that recovered trafficking and function of ATP7B-H1069Q by impairing its exposure to the HSP70 proteostatic network. Our findings suggest that HSP70-mediated degradation can be safely targeted with domperidone to rescue ER-retained ATP7B mutants and, hence, to counter the onset of Wilson disease.
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Баязутдинова, Г. М., О. А. Щагина, А. С. Карунас, А. В. Поляков, and Э. К. Хуснутдинова. "The method of screening for frequent insertion/deletion in gene." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 1() (March 4, 2020): 8–12. http://dx.doi.org/10.25557/2073-7998.2019.01.8-12.
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Болезнь Вильсона-Коновалова - наследственное аутосомно-рецессивное заболевание. Причиной болезни являются патоген- ные варианты в гене ATP7B , среди которых нередко встречаются инсерции и делеции. В данной работе проведено исследова- ние частот инсерций/делеций в гене АТР7В в выборке пробандов с направительным диагнозом «болезнь Вильсона-Коновалова». На основании полученных данных создана простая и информативная система поиска частых инсерций/делеций в этом гене. В систему вошли следующие инсерции/делеции: c.1770insT, c.2304insC, c.2532delA, c.3036insC, c.3402delC, c.3627_3642del4, c.3649_3654del6, c.[3942delCA;3947delG]. Их суммарная частота составила 14,9%. Wilson-Konovalov’s disease (WD) is a rare inborn disease characterized by excess accumulation of copper in parenchymal tissues. WD is caused by pathogenic variants in the ATP7B gene, such as missense variants, insertion/deletion. The results of study of allelic frequencies of insertion/deletion in ATP7B gene in Russian WD-patients are presented in this research. The mutations: c.1770insT, c.2304insC, c.2532delA, c.3036insC, c.3402delC, c.3627_3642del4, c.3649_3654del6, c.[3942delCA;3947delG] were included to the screening system for frequent ins/ del in ATP7B gene.
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Ogórek, Mateusz, Małgorzata Lenartowicz, Rafał Starzyński, et al. "Atp7a and Atp7b regulate copper homeostasis in developing male germ cells in mice." Metallomics 9, no. 9 (2017): 1288–303. http://dx.doi.org/10.1039/c7mt00134g.
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Tillquist, Nicole M., Meghan P. Thorndyke, Tyler A. Thomas, Stephen J. Coleman, and Terry E. Engle. "PSVII-12 Investigating the influence of copper supplementation on copper homeostatic genes in bovine liver." Journal of Animal Science 98, Supplement_4 (2020): 308. http://dx.doi.org/10.1093/jas/skaa278.550.
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Abstract The objective of this experiment was to investigate the influence of copper (Cu) supplementation on Cu homeostatic genes in bovine liver. Liver samples were obtained from multiparous cows (n = 3 cows per treatment) from a previous experiment. Treatments consisted of: 1) no supplemental Cu (-Cu; total diet contained 7.0 mg Cu/kg DM) and 2) 3 mg Cu/kg DM (+Cu; total diet contained 10.0 mg Cu/kg DM). Cows were fed their respective diets for 420 d. Liver samples were harvested immediately upon slaughter, rinsed with phosphate-buffered saline solution, diced into small pieces, and placed into RNAlater and frozen at -80°C. Total RNA was extracted from all samples, and quantitative RT-PCR was used to determine the abundance of transcripts for proteins involved in Cu homeostasis in liver tissue. The target transcripts were: ALDH2, APOA1, ATOX1, ATP7A, ATP7B, BHMT, BLVRB, CA2, CCS, COX17, CTR1, ELN, GAPDH, GLUD1, GSS, LOXL1, PDIA3, SOD1, SOD3. The relative abundance of APOA1, ATOX1, ATP7B, BLVRB, CTR1, GLUD1, LOXL1, and SOD3 mRNA was greater (P &lt; 0.05) in cows receiving supplemental Cu when compared to cattle not receiving supplemental Cu. These data indicate possible differences in Cu homeostasis in the liver based on Cu supplementation. Further investigation is warranted to determine if a difference in the relative abundance of identified transcripts are related to differences in associated protein production and function.
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Скрябин, Н. А., О. Ю. Васильева, А. А. Сивцев, et al. "ATP7B gene study using massively parallel sequencing in patients with Wilson's disease." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 7(216) (July 30, 2020): 97–98. http://dx.doi.org/10.25557/2073-7998.2020.07.97-98.
Full textAbstract:
Болезнь Вильсона-Коновалова (БВК) - аутосомно-рецессивное заболевание, развивающееся вследствие накопления меди в организме при повреждениях гена АТР7В. В настоящем исследовании проводился поиск мутаций в этом гене методом массового параллельного секвенирования у больных с БВК. Для целевого обогащения интересуемых регионов была разработана панель праймеров для ПЦР длинных фрагментов. У 6 пациентов из 12 проанализированных выявлены патогенные и вероятно патогенные варианты нуклеотидной последовательности гена АТР7В. Полученные результаты указывают на то, что разработанный метод таргетного массового параллельного секвенирования позволяет эффективно выявлять мутации в гене ATP7B. Wilson’s disease is an autosomal recessive disease that develops as a result of the accumulation of copper in the organism when the ATP7B gene is damaged. The present study searched for mutations in this gene using massively parallel sequencing in patients with Wilson’s disease. For targeted enrichment of the regions of interest, a primer panel for PCR of long fragments was developed. In 6 patients out of 12 analyzed, pathogenic and probably pathogenic variants of the nucleotide sequence of the ATP7B gene were identified. The obtained results indicate that the developed method of targeted massively parallel sequencing allows efficient detection of mutations in the ATP7B gene.
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Ilyechova, Ekaterina Y., Irina V. Miliukhina, Marina N. Karpenko, Iurii A. Orlov, Ludmila V. Puchkova, and Sergey A. Samsonov. "Case of Early-Onset Parkinson’s Disease in a Heterozygous Mutation Carrier of the ATP7B Gene." Journal of Personalized Medicine 9, no. 3 (2019): 41. http://dx.doi.org/10.3390/jpm9030041.
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In this paper, we report a clinically proven case of Parkinson’s disease (PD) with early onset in a patient who is a heterozygous mutation carrier of ATP7B (the Wilson’s disease gene). The patient was observed from 2011 to 2018 in the Center for Neurodegenerative Diseases, Institute of Experimental Medicine (St. Petersburg, Russia). During this period, the patient displayed aggravation of PD clinical symptoms that were accompanied by a decrease in the ceruloplasmin concentration (from 0.33 to 0.27 g/L) and an increase in serum nonceruloplasmin copper, which are typical of the late stages of Wilson’s disease. It was found that one of the alleles of exon 14 in the ATP7B gene, which partially codes of the nucleotide-binding domain (N-domain), carries a mutation not previously reported corresponding to Cys1079Gly substitution. Alignment of the ATP7B N-domain amino acid sequences of representative vertebrate species has shown that the Cys at 1079 position is conserved throughout the evolution. Molecular dynamic analysis of a polypeptide with Cys1079Gly substitution showed that the mutation causes profound conformational changes in the N-domain, which could potentially lead to impairment of its functions. The role of ATP7B gene mutations in PD development is discussed.