A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism

Maya Schushan, Ashima Bhattacharjee, Nir Ben-Tal, Svetlana Lutsenko

Research output: Contribution to journalArticle

Abstract

The copper-transporting ATPase ATP7B has an essential role in human physiology, particularly for the liver and brain function. Inactivation of ATP7B is associated with a severe hepato-neurologic disorder, Wilson disease (WD). Hundreds of WD related mutations have been identified in ATP7B to date. The low frequency and the compound-heterozygous nature of causative mutations complicate the analysis of individual mutants and the establishment of genotype-phenotype correlations. To facilitate studies of disease-causing mutations and mechanistic understanding of WD, we have homology-modelled the ATP7B core (residues 643-1377) using the recent structure of the bacterial copper-ATPase LCopA as a template. The model, supported by evolutionary conservation and hydrophobicity analysis, as well as existing and new mutagenesis data, allows molecular interpretations of experimentally characterized clinical mutations. We also illustrate that structure and conservation can be used to grade potential deleterious effects for many WD mutations, which were clinically detected but have not yet been experimentally characterized. Finally, we compare the structural features of ATP7B and LCopA and discuss specific features of the eukaryotic copper pump.

Original languageEnglish (US)
Pages (from-to)669-678
Number of pages10
JournalMetallomics
Volume4
Issue number7
DOIs
StatePublished - 2012

Fingerprint

Hepatolenticular Degeneration
Structural Models
Adenosine Triphosphatases
Copper
Mutation
Conservation
Bacterial Structures
Mutagenesis
Physiology
Genetic Association Studies
Hydrophobicity
Nervous System Diseases
Hydrophobic and Hydrophilic Interactions
Liver
Brain
Pumps

ASJC Scopus subject areas

  • Biomaterials
  • Metals and Alloys
  • Chemistry (miscellaneous)
  • Biochemistry
  • Biophysics

Cite this

A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism. / Schushan, Maya; Bhattacharjee, Ashima; Ben-Tal, Nir; Lutsenko, Svetlana.

In: Metallomics, Vol. 4, No. 7, 2012, p. 669-678.

Research output: Contribution to journalArticle

@article{ba183a63b1a44bccaf1d984c0b83a6df,
title = "A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism",
abstract = "The copper-transporting ATPase ATP7B has an essential role in human physiology, particularly for the liver and brain function. Inactivation of ATP7B is associated with a severe hepato-neurologic disorder, Wilson disease (WD). Hundreds of WD related mutations have been identified in ATP7B to date. The low frequency and the compound-heterozygous nature of causative mutations complicate the analysis of individual mutants and the establishment of genotype-phenotype correlations. To facilitate studies of disease-causing mutations and mechanistic understanding of WD, we have homology-modelled the ATP7B core (residues 643-1377) using the recent structure of the bacterial copper-ATPase LCopA as a template. The model, supported by evolutionary conservation and hydrophobicity analysis, as well as existing and new mutagenesis data, allows molecular interpretations of experimentally characterized clinical mutations. We also illustrate that structure and conservation can be used to grade potential deleterious effects for many WD mutations, which were clinically detected but have not yet been experimentally characterized. Finally, we compare the structural features of ATP7B and LCopA and discuss specific features of the eukaryotic copper pump.",
author = "Maya Schushan and Ashima Bhattacharjee and Nir Ben-Tal and Svetlana Lutsenko",
year = "2012",
doi = "10.1039/c2mt20025b",
language = "English (US)",
volume = "4",
pages = "669--678",
journal = "Metallomics",
issn = "1756-5901",
publisher = "Royal Society of Chemistry",
number = "7",

}

TY - JOUR

T1 - A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism

AU - Schushan, Maya

AU - Bhattacharjee, Ashima

AU - Ben-Tal, Nir

AU - Lutsenko, Svetlana

PY - 2012

Y1 - 2012

N2 - The copper-transporting ATPase ATP7B has an essential role in human physiology, particularly for the liver and brain function. Inactivation of ATP7B is associated with a severe hepato-neurologic disorder, Wilson disease (WD). Hundreds of WD related mutations have been identified in ATP7B to date. The low frequency and the compound-heterozygous nature of causative mutations complicate the analysis of individual mutants and the establishment of genotype-phenotype correlations. To facilitate studies of disease-causing mutations and mechanistic understanding of WD, we have homology-modelled the ATP7B core (residues 643-1377) using the recent structure of the bacterial copper-ATPase LCopA as a template. The model, supported by evolutionary conservation and hydrophobicity analysis, as well as existing and new mutagenesis data, allows molecular interpretations of experimentally characterized clinical mutations. We also illustrate that structure and conservation can be used to grade potential deleterious effects for many WD mutations, which were clinically detected but have not yet been experimentally characterized. Finally, we compare the structural features of ATP7B and LCopA and discuss specific features of the eukaryotic copper pump.

AB - The copper-transporting ATPase ATP7B has an essential role in human physiology, particularly for the liver and brain function. Inactivation of ATP7B is associated with a severe hepato-neurologic disorder, Wilson disease (WD). Hundreds of WD related mutations have been identified in ATP7B to date. The low frequency and the compound-heterozygous nature of causative mutations complicate the analysis of individual mutants and the establishment of genotype-phenotype correlations. To facilitate studies of disease-causing mutations and mechanistic understanding of WD, we have homology-modelled the ATP7B core (residues 643-1377) using the recent structure of the bacterial copper-ATPase LCopA as a template. The model, supported by evolutionary conservation and hydrophobicity analysis, as well as existing and new mutagenesis data, allows molecular interpretations of experimentally characterized clinical mutations. We also illustrate that structure and conservation can be used to grade potential deleterious effects for many WD mutations, which were clinically detected but have not yet been experimentally characterized. Finally, we compare the structural features of ATP7B and LCopA and discuss specific features of the eukaryotic copper pump.

UR - http://www.scopus.com/inward/record.url?scp=84863708072&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863708072&partnerID=8YFLogxK

U2 - 10.1039/c2mt20025b

DO - 10.1039/c2mt20025b

M3 - Article

C2 - 22692182

AN - SCOPUS:84863708072

VL - 4

SP - 669

EP - 678

JO - Metallomics

JF - Metallomics

SN - 1756-5901

IS - 7

ER -