Hepatocyte-specific localization and copper-dependent trafficking of the Wilson’s disease protein in the liver

1999 ◽  
Vol 276 (3) ◽  
pp. G639-G646 ◽  
Author(s):  
Mark Schaefer ◽  
Robin G. Hopkins ◽  
Mark L. Failla ◽  
Jonathan D. Gitlin
Keyword(s):  
Wilson’S Disease ◽  
Neuronal Degeneration ◽  
Copper Metabolism ◽  
Wilson's Disease ◽  
Polyclonal Antiserum ◽  
Copper Excretion ◽  
Hepatic Expression ◽  
Hepatic Copper ◽  
Disease Protein

Wilson’s disease is an inherited disorder of copper metabolism characterized by hepatic cirrhosis and neuronal degeneration. In this current study, a polyclonal antiserum specific for the Wilson’s disease ATPase was used to examine the hepatic expression of this protein. Immunoblot analysis of lysates from human and rat liver detected a single 165-kDa protein, which by immunofluorescence was present only in hepatocytes and localized predominantly to the trans-Golgi network and exclusively in this compartment under low hepatic copper concentrations. Although hepatic copper concentration had no effect on the steady-state levels of the Wilson’s disease protein, copper administration in vivo resulted in redistribution of this protein to a cytoplasmic vesicular compartment localized toward the hepatocyte canalicular membrane. The relative abundance of the Wilson’s disease protein in the liver was found to be greatest in the fetus before the onset of biliary copper excretion. Taken together, these studies reveal a novel posttranslational mechanism of copper homeostasis in vivo consistent with the proposed function of the Wilson’s disease protein in holoceruloplasmin biosynthesis and biliary copper excretion and of relevance to the broad clinical heterogeneity observed in this disease.

scholarly journals Wilson’s Disease Presenting in Late Adult Life

2021 ◽  
pp. 142-146
Author(s):  
Wafa AlDhaleei ◽  
Maryam AlAhmad ◽  
Ibrahim Alhosani
Keyword(s):  
Wilson’S Disease ◽  
Adult Life ◽  
Copper Metabolism ◽  
Wilson's Disease ◽  
Serum Copper ◽  
Hepatic Copper ◽  
Urinary Copper ◽  
Clinical Presentations ◽  
Function Impairment ◽  
Diagnostic Management

Wilson’s disease (WD) is an autosomal recessive disease affecting the copper metabolism resulting in various clinical presentations. Diagnosis includes the presence of low serum copper and ceruloplasmin concentrations, increased urinary copper excretion, and/or increased hepatic copper concentrations. Yet, genetic testing remains diagnostic. Management includes copper chelating agents and liver transplant in advance cases. We report a case of WD presenting with liver function impairment in late adult life and started on treatment. Therefore, early diagnosis and treatment of WD can prevent related complications.

scholarly journals Lysosomal Defect of Hepatic Copper Excretion in Wilson's Disease (Hepatolenticular Degeneration)

1973 ◽  
Vol 64 (1) ◽  
pp. 99-105 ◽  
Author(s):  
Irmin Sternlieb ◽  
C.J.A. van den Hamer ◽  
Anatol G. Morell ◽  
Seymour Alpert ◽  
Gregory Gregoriadis ◽  
...  
Keyword(s):  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Hepatolenticular Degeneration ◽  
Copper Excretion ◽  
Hepatic Copper

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.

Uneven hepatic copper distribution in Wilson's disease

1995 ◽  
Vol 22 (3) ◽  
pp. 303-308 ◽  
Author(s):  
Gavino Faa ◽  
Valeria Nurchi ◽  
Luigi Demelia ◽  
Rossano Ambu ◽  
Giuseppina Parodo ◽  
...  
Keyword(s):  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Hepatic Copper ◽  
Copper Distribution

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.

A comparison of copper-loading disease in Bedlington terriers and Wilson's disease in humans

1982 ◽  
Vol 243 (3) ◽  
pp. G226-G230 ◽  
Author(s):  
L. C. Su ◽  
S. Ravanshad ◽  
C. A. Owen ◽  
J. T. McCall ◽  
P. E. Zollman ◽  
...  
Keyword(s):  
Copper Concentration ◽  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Normal Brain ◽  
Glutamic Pyruvic Transaminase ◽  
Serum Glutamic Pyruvic Transaminase ◽  
Hepatic Copper ◽  
Erythrocyte Survival ◽  
Ceruloplasmin Activity

Eleven Bedlington terriers were found to have a mean hepatic copper concentration of 6,321 micrograms/g dry wt (normal, 200 micrograms/g dry wt) and renal copper concentration that was three or four times normal. Brain copper levels were normal in younger dogs, were elevated in two older dogs, and were 100 times normal in one dog that died of the disease. Increased concentrations of copper in the liver, kidney, and brain also characterize Wilson's disease. Erythrocyte survival was normal in three affected dogs, but serum glutamic-pyruvic transaminase levels were usually elevated. Unlike the hypoceruloplasminemia of patients with Wilson's disease, plasma ceruloplasmin activity was not only normal but was also slightly elevated in the terriers. Despite their normal or excessive ceruloplasmin, the Bedlington terriers could convert ionic 64Cu to radioceruloplasmin but did so only very slowly. These dogs accumulated significantly more 64Cu in their livers than normal, much like patients with Wilson's disease do before symptoms develop.

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.

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