scholarly journals The Role of the Invariant His-1069 in Folding and Function of the Wilson's Disease Protein, the Human Copper-transporting ATPase ATP7B

2003 ◽  
Vol 278 (15) ◽  
pp. 13302-13308 ◽  
Author(s):  
Ruslan Tsivkovskii ◽  
Roman G. Efremov ◽  
Svetlana Lutsenko
Keyword(s):  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Disease Protein ◽  
And Function

The Wilson's disease protein expressed in Sf9 cells is phosphorylated

2002 ◽  
Vol 30 (4) ◽  
pp. 739-741 ◽  
Author(s):  
S. M. Vanderwerf ◽  
S. Lutsenko
Keyword(s):  
Mammalian Cells ◽  
Wilson’S Disease ◽  
Insect Cells ◽  
Physiological Role ◽  
Wilson's Disease ◽  
Copper Transporter ◽  
Mammalian Cell Lines ◽  
Disease Protein ◽  
Baculovirus System

The Wilson's disease protein (WNDP), a copper transporter, is a crucial mediator of copper homoeostasis in mammalian cells. We recently found that changes in copper concentration regulate the phosphorylation level of WNDP. WNDP phosphorylation was observed in several mammalian cell lines, suggesting that a common phosphorylation pathway exists in these cells. Here we demonstrate that WNDP expressed in Sf9 insect cells is also phosphorylated, as evidenced by metabolic labelling of these cells with [32P]Pi. Because the baculovirus system allows us to generate large amounts of protein, we are using this expression method to isolate WNDP and map the sites of WNDP phosphorylation. The identification of phosphorylation sites is the first step towards understanding the physiological role of WNDP phosphorylation.

The Need for Consensus About Liver Transplantation For Patients With Neuropsychiatric Wilson’s Disease

2021 ◽  
pp. 152692482110028
Author(s):  
Alberto Ferrarese ◽  
Patrizia Burra
Keyword(s):  
Liver Transplantation ◽  
Patient Outcomes ◽  
Wilson’S Disease ◽  
Therapeutic Option ◽  
Copper Metabolism ◽  
Wilson's Disease ◽  
Published Data ◽  
Neurological Improvement ◽  
Effective Therapeutic Option

Liver transplantation is considered an effective therapeutic option for Wilson’s disease (WD) patients with hepatic phenotype, since it removes the inherited defects of copper metabolism, and is associated with excellent graft and patient outcomes. The role of liver transplantation in WD patients with mixed hepatic and neuropsychiatric phenotype has remained controversial over time, mainly because of high post-operative complications, reduced survival and a variable, unpredictable rate of neurological improvement. This article critically discusses the recently published data in this field, focussing in more detail on isolated neuropsychiatric phenotype as a potential indication for liver transplantation in WD patients.

Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification

2013 ◽  
Vol 454 (1) ◽  
pp. 147-156 ◽  
Author(s):  
Nataliya V. Dolgova ◽  
Sergiy Nokhrin ◽  
Corey H. Yu ◽  
Graham N. George ◽  
Oleg Y. Dmitriev
Keyword(s):  
Metal Binding ◽  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Binding Domain ◽  
Binding Motif ◽  
Copper Chaperone ◽  
Copper Binding ◽  
Copper Transporters ◽  
Metal Binding Domain ◽  
Disease Protein

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.

scholarly journals Functional Properties of the Copper-transporting ATPase ATP7B (The Wilson's Disease Protein) Expressed in Insect Cells

2001 ◽  
Vol 277 (2) ◽  
pp. 976-983 ◽  
Author(s):  
Ruslan Tsivkovskii ◽  
John F. Eisses ◽  
Jack H. Kaplan ◽  
Svetlana Lutsenko
Keyword(s):  
Functional Properties ◽  
Wilson’S Disease ◽  
Insect Cells ◽  
Wilson's Disease ◽  
Disease Protein

scholarly journals Molecular modelling of the nucleotide-binding domain of Wilson's disease protein: location of the ATP-binding site, domain dynamics and potential effects of the major disease mutations

2004 ◽  
Vol 382 (1) ◽  
pp. 293-305 ◽  
Author(s):  
Roman G. EFREMOV ◽  
Yuri A. KOSINSKY ◽  
Dmitry E. NOLDE ◽  
Ruslan TSIVKOVSKII ◽  
Alexander S. ARSENIEV ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Modelling ◽  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Binding Domain ◽  
Atp Binding ◽  
Disease Mutations ◽  
Disease Protein ◽  
Dynamics Simulations

WNDP (Wilson's disease protein) is a copper-transporting ATPase that plays an essential role in human physiology. Mutations in WNDP result in copper accumulation in tissues and cause a severe hepato-neurological disorder known as Wilson's disease. Several mutations were surmised to affect the nucleotide binding and hydrolysis by WNDP; however, how the nucleotides bind to normal and mutated WNDP remains unknown. To aid such studies, we performed the molecular modelling of the spatial structure and dynamics of the ATP-binding domain of WNDP and its interactions with ATP. The three-dimensional models of this domain in two conformations were built using the X-ray structures of the Ca2+-ATPase in the E1 and E2 states. To study the functional aspects of the models, they were subjected to long-term molecular dynamics simulations in an explicit solvent; similar calculations were performed for the ATP-binding domain of Ca2+-ATPase. In both cases, we found large-scale motions that lead to significant changes of distances between several functionally important residues. The ATP docking revealed two possible modes of ATP binding: via adenosine buried in the cleft near residues H1069, R1151 and D1164, and via phosphate moiety ‘anchored’ by H-bonds with residues in the vicinity of catalytic D1027. Furthermore, interaction of ATP with both sites occurs if they are spatially close to each other. This may be achieved after relative domain motions of the ‘closure’ type observed in molecular dynamics simulations. The results provide a framework for analysis of disease mutations and for future mutagenesis studies.

scholarly journals Cholangiocarcinoma in Wilson’s Disease – a Case Report

2017 ◽  
Vol 26 (3) ◽  
pp. 305-308
Author(s):  
Dániel Németh ◽  
Anikó Folhoffer ◽  
Gábor Smuk ◽  
Béla Kajtár ◽  
Tamás Tornóczky ◽  
...  
Keyword(s):  
Wilson’S Disease ◽  
Treatment Initiation ◽  
Clinical Symptoms ◽  
Rapid Development ◽  
Primary Tumour ◽  
Chelating Agent ◽  
Wilson's Disease ◽  
Protective Role ◽  
Ceruloplasmin Level

It has been suggested that hepatobiliary carcinomas are less frequent in Wilson’s disease (WD) than in liver diseases of other etiology. However, the protective role of copper against malignancies is debated. Only a few cases of cholangiocarcinoma (CCC) in WD have been published. Here we report on a case of a 47-year-old male H1069Q homozygous, Kayser-Fleischer ring positive WD patient with a low ceruloplasmin level who was followed up and treated with chelating agents throughout nine years. The patient presented with neurological symptoms and liver cirrhosis at diagnosis. Clinical symptoms regressed after the treatment initiation. Rapidly developed tumour metastases were found in the bones, lung and liver (without jaundice). Autopsy revealed cholangiocarcinoma as the primary tumour confirmed by strong CK7 positivity and glypican-3 negativity. The curiosity of the presented case is the very rapid development of CCC despite continuous chelating agent therapy.Abbreviations: CCC: cholangiocarcinoma; HCC: hepatocellular carcinoma; WD: Wilson disease.

Biochemistry of the Wilson's Disease Protein

2003 ◽  
pp. 035-051
Author(s):  
Svetlana Lutsenko ◽  
Ruslan Tsivkovskii ◽  
Matthew J. Cooper ◽  
Brian C. MacArthur ◽  
Hans-Peter Bächinger
Keyword(s):  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Disease Protein

Wilson's Disease: The Role of Penicillamine

1969 ◽  
Vol 134 (11) ◽  
pp. 1336-1339
Author(s):  
Benjamin M. Carmichael
Keyword(s):  
Wilson’S Disease ◽  
Wilson's Disease

scholarly journals MORPHOLOGIC ALTERATIONS PRODUCED BY COPPER IN NEURAL TISSUES WITH CONSIDERATION OF THE ROLE OF THE METAL IN THE PATHOGENESIS OF WILSON'S DISEASE

1961 ◽  
Vol 113 (6) ◽  
pp. 997-1004 ◽  
Author(s):  
F. Stephen Vogel ◽  
John W. Evans
Keyword(s):  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Neural Function ◽  
Cupric Sulfate ◽  
Neurologic Manifestations ◽  
Myelin Sheaths ◽  
Neural Tissues ◽  
Histologic Changes

The injection into the cerebrospinal fluid of cats of 52 to 208 gamma of copper in the form of an albumin complex or as cupric sulfate, was followed by small elevations in the content of metal in the neural tissues, but regularly and promptly produced persistent quadriplegia and conspicuous histologic changes. Smaller amounts of copper caused less, or no, neurologic manifestations or histologic alterations. The earliest lesions were essentially unaccompanied by inflammation and were initially characterized by hydropic swelling of the myelin sheaths. They progressed rapidly to focal necrosis of all parenchymal components with marked degeneration of myelin and axis cylinders in the peripheral margins of the spinal cord, brain stem, mid-brain, and cerebrum. These histologic changes did not occur in neural tissues incubated in vitro in solutions of the copper-albumin complex. They did not appear in animals injected intraventricularly with ferric sulfate or saccharated iron. Considered together, the findings make it clear that copper in concentrations comparable to those present in the neural tissues of patients with Wilson's disease has the property of profoundly altering neural function and causing conspicuous morphologic alterations.

Localization of the Wilson's disease protein in human liver

1999 ◽  
Vol 117 (6) ◽  
pp. 1380-1385 ◽  
Author(s):  
Mark Schaefer ◽  
Han Roelofsen ◽  
Henk Wolters ◽  
Walter J. Hofmann ◽  
Michael Müller ◽  
...  
Keyword(s):  
Human Liver ◽  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Disease Protein
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