Distinct Wilson’s Disease Mutations in ATP7B Are Associated With Enhanced Binding to COMMD1 and Reduced Stability of ATP7B

Bie, Prim de; Sluis, Bart van de; Burstein, Ezra; Berghe, Peter V. E. van den; Müller, Patricia; Berger, Ruud; Gitlin, Jonathan D.; Wijmenga, Cisca; Klomp, Leo W. J.

doi:10.1053/j.gastro.2007.07.020

Cited by 138 publications

(177 citation statements)

References 36 publications

Supporting

Mentioning

164

Contrasting

Unclassified

Order By: Relevance

“…Constructs and Reagents-ATP7B cDNA constructs encoding WT ATP7B, ATP7B(MBD 1-6del), and ATP7B(MBD 3-5del), and N-terminal FLAG-tagged WT-ATP7B-FLAG and ATP7B-G85V-FLAG were generated previously (23,24). Clusterin cDNA in pIREShyg1 (Clontech) was kindly provided by Saverio Bettuzzi (University of Parma).…”

Section: Methodsmentioning

confidence: 99%

Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B

Materia

Cater

Klomp

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The copper-transporting P 1B -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.

show abstract

Section: Methodsmentioning

confidence: 99%

Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B

Materia

Cater

Klomp

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, the protein COMMD1 (Copper Metabolism Murr1 Domain) was recently shown to interact with the metal-binding domains of ATP7B and this appeared to regulate overall ATP7B stability via the ER degradation pathway (de Bie et al 2007;Materia et al 2012). The binding sites on neither protein nor the physical mechanism resulting in ER degradation (interaction causing protein destabilization or triggering of a cellular signal) are known.…”

Section: Interactions With Other Proteins and New Functionsmentioning

confidence: 99%

Unresolved questions in human copper pump mechanisms

Wittung-Stafshede

2015

Quart. Rev. Biophys.

View full text Add to dashboard Cite

Abstract. Copper (Cu) is an essential transition metal providing activity to key enzymes in the human body. To regulate the levels and avoid toxicity, cells have developed elaborate systems for loading these enzymes with Cu. Most Cu-dependent enzymes obtain the metal from the membrane-bound Cu pumps ATP7A/B in the Golgi network. ATP7A/B receives Cu from the cytoplasmic Cu chaperone Atox1 that acts as the cytoplasmic shuttle between the cell membrane Cu importer, Ctr1 and ATP7A/B. Biological, genetic and structural efforts have provided a tremendous amount of information for how the proteins in this pathway work. Nonetheless, basic mechanistic-biophysical questions (such as how and where ATP7A/B receives Cu, how ATP7A/B conformational changes and domain-domain interactions facilitate Cu movement through the membrane, and, finally, how target polypeptides are loaded with Cu in the Golgi) remain elusive. In this perspective, unresolved inquiries regarding ATP7A/B mechanism will be highlighted. The answers are important from a fundamental view, since mechanistic aspects may be common to other metal transport systems, and for medical purposes, since many diseases appear related to Cu transport dysregulation.

show abstract

“…Although it has been reported that COMMD1 binds Cu 2? [112], a direct and copper-independent interaction between the amino terminus of ATP7B and COMMD1 has been characterized [113,114]. Transient knockdown of COMMD1 by RNA interference results in increased cellular copper levels in HEK293T cells [115][116][117].…”

Section: Regulation Of Copper Transport By Protein-protein Interactionsmentioning

confidence: 99%

“…Together, these data suggest that ATP7B and COMMD1 cooperate in cellular copper export, which might be the underlying defect in Bedlington terriers affected by copper toxicosis. Interestingly, the interaction between COMMD1 and ATP7B is markedly increased when Wilson-disease-associated mutations of ATP7B are present [114,118]. These mutations are associated with misfolding, mislocalization of ATP7B to the endoplasmic reticulum, and decreased protein expression due to increased proteasomal degradation.…”

Section: Regulation Of Copper Transport By Protein-protein Interactionsmentioning

confidence: 99%

See 1 more Smart Citation

Posttranslational regulation of copper transporters

Berghe

Klomp

2009

J Biol Inorg Chem

View full text Add to dashboard Cite

Distinct Wilson’s Disease Mutations in ATP7B Are Associated With Enhanced Binding to COMMD1 and Reduced Stability of ATP7B

Cited by 138 publications

References 36 publications

Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B

Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B

Unresolved questions in human copper pump mechanisms

Posttranslational regulation of copper transporters

Contact Info

Product

Resources

About