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

doi:10.1039/c2mt20025b

Cited by 58 publications

(61 citation statements)

References 62 publications

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“…are shown. (20). Therefore, it was particularly interesting that ATP7B S653Y is located within a region (G 621 -S 668 ) following MBD6 and encompassing TM1 that is highly conserved in vertebrates (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Current treatments focus on controlling the amount of copper in the body with chelating agents, which have a long list of side effects (44,45); however, new approaches that focus on correcting defective proteins could provide a novel treatment strategy (46). Recent homology-modeling studies have provided a convenient tool for in silico structure/function analysis of the ATP7A (47) and ATP7B cores (20,47). In an effort to improve functional predictions of WD patient mutations located within the core region, a grading strategy was developed based on the ATP7B model/structure (20) and suggested as a guide for selecting relevant assays useful for elucidating functional defects of WD missense mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Recent homology-modeling studies have provided a convenient tool for in silico structure/function analysis of the ATP7A (47) and ATP7B cores (20,47). In an effort to improve functional predictions of WD patient mutations located within the core region, a grading strategy was developed based on the ATP7B model/structure (20) and suggested as a guide for selecting relevant assays useful for elucidating functional defects of WD missense mutations. Although epigenetics, modifier loci, and environment likely contribute to the range of WD clinical phenotypes (48), we propose that a combination of clinical and genetic studies together with in depth analyses would allow for functional classification of WD mutations similar to the classification system used for Cystic Fibrosis mutations (49), and might allow for the development of other treatment strategies, which may possibly correct a functionally defective protein and improve patient management.…”

Section: Discussionmentioning

confidence: 99%

“…The published structural model of ATP7B (20) was used as a template to model the S653 substitutions using SWISS-MODEL (51). The solvent accessible surface area for the functional groups in positions 653, 710, and 713 was calculated using the AREAIMOL program from the CCP4i suite (52).…”

Section: Methodsmentioning

confidence: 99%

“…2C) but was unable to traffic in response to copper, we hypothesized that TM1 harboring S653 played a specific and important role in regulated trafficking of ATP7B. To better understand what this role could be, we examined structural characteristics of this region using the recently generated homology model of ATP7B (20). Analysis of the ATP7B model (Fig.…”

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confidence: 99%

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Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Braiterman¹,

Murthy²,

Jayakanthan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Wilson disease (WD) is a monogenic autosomal-recessive disorder of copper accumulation that leads to liver failure and/or neurological deficits. WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper out of cells by trafficking from the TGN to the plasma membrane. To date, most WD mutations have been shown to disrupt ATP7B activity and/or stability. Using a multidisciplinary approach, including clinical analysis of patients, cell-based assays, and computational studies, we characterized a patient mutation, ATP7B S653Y , which is stable, does not disrupt Cu(I) transport, yet renders the protein unable to exit the TGN. Bulky or charged substitutions at position 653 mimic the phenotype of the patient mutation. Molecular modeling and dynamic simulation suggest that the S653Y mutation induces local distortions within the transmembrane (TM) domain 1 and alter TM1 interaction with TM2. S653Y abolishes the trafficking-stimulating effects of a secondary mutation in the N-terminal apical targeting domain. This result indicates a role for TM1/ TM2 in regulating conformations of cytosolic domains involved in ATP7B trafficking. Taken together, our experiments revealed an unexpected role for TM1/TM2 in copper-regulated trafficking of ATP7B and defined a unique class of WD mutants that are transport-competent but trafficking-defective. Understanding the precise consequences of WD-causing mutations will facilitate the development of advanced mutation-specific therapies.ceruloplasmin | interdomain interactions | molecular dynamics

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Braiterman¹,

Murthy²,

Jayakanthan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Molecular Genetics of Wilson Disease

Roberts

2013

Encyclopedia of Life Sciences

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Wilson disease is an autosomal‐recessive genetic disorder of hepatocellular copper disposition. It is rare but has a worldwide distribution. It is clinically diverse. Disease patterns include various kinds of liver disease; neurological movement disorders and psychiatric disease including psychosis, and less commonly recurrent haemolytic anaemia, osseomuscular abnormalities and cardiac dysrhythmias. The classic eye finding, the Kayser–Fleischer ring, has no functional impact. Thus far, only one gene has been identified whose mutations are causal for Wilson disease, ATP7B on chromosome 13q14.3, cloned in 1993. More than 500 mutations have been identified. The encoded protein is a metal‐transporting P‐type adenosine triphosphatase (ATPase), the Wilson ATPase, similar to copper transporters across the phyla. Simple genotypic explanation for the phenotypic diversity does not exist. The important genotype–phenotype correlation is that if the Wilson ATPase is absent or nonfunctional, severe disease (usually hepatic) commonly develops in the first decade of life. Clinically evident Wilson disease is fatal if not treated. The broad age range of diagnoses (3–80+ years) raises the question of incomplete penetrance, an issue along with gene modifiers currently under investigation. The possibility that mutations in other genes may result in Wilson disease has not been entirely eliminated. The contribution of ATP7B to non‐Wilsonian diseases is being determined. Key Concepts: Wilson disease is a rare (30 per million population, on average) autosomal‐recessive disorder of hepatic copper disposition. Wilson disease can present as almost any form of hepatic disease, or as neurological movement disorders, or as psychiatric disease. Genetic diagnosis is definitive; clinical application of genetic findings requires skilled interpretation; success rate for identifying one or both mutations can be highly variable. Most affected individuals are compound heterozygotes. Genetic testing is most efficient for investigating first‐degree relatives, who must be assessed for Wilson disease once a single family member has been diagnosed with Wilson disease. Wilson disease is an example of ‘endogenous hepatotoxicity’ where a normal component of the functioning organism is mishandled and becomes toxic. The mechanism of liver (and likely brain) damage involves oxidative stress with damage to mitochondria; apoptosis is typical. Concepts relating to drug‐induced hepatotoxicity are highly relevant to understanding the mechanism of damage and devising treatments. Metalloproteomics is a research strategy for examining copper disposition in normal and abnormal models/organisms. More than 500 mutations in ATP7B have been identified. These are mainly missense mutations, and less frequently small deletions or insertions, nonsense or splice‐site mutations. In contrast, the homologous gene ATP7A , abnormal in the X‐linked recessive disorder Menkes disease (with copper insufficiency), displays mainly large deletions. Predictably, the phenotypic variation depends on complex factors besides the genotype. The only important genotype–phenotype correlation is that severe disease (usually hepatic) typically develops very early in life if the Wilson ATPase is absent or nonfunctional. A convincing example of this correlation is provided by comparison of the Atp7b ‐knockout mouse and the toxic milk (tx‐j) mouse, which has a point mutation. Few modifying genes have been identified. Candidates include apolipoprotein E, human prion gene and BIRC4/XIAP. Females seem to have more severe Wilson disease. Other disorders of copper disposition exist. These include defects in ceruloplasmin production (aceruloplasminaemia and AT‐1 defect), various congenital glycosylation disorders, Indian childhood cirrhosis and its variants. In the Bedlington terrier, hepatic copper toxicosis is usually related to mutations in the gene for COMMD1. ATP7B may play a secondary role in some forms of Alzheimer disease. The Wilson ATPase plays a direct role in the hepatocellular handling of platinum compounds such as cisplatin.

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Copper TransportingATPases in Mammalian Cells

Yang

Lutsenko

2004

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Copper‐transporting ATP ases ( Cu‐ATPases ) are essential for growth and development of mammalian organisms. These ubiquitous and evolutionarily conserved transporters participate in the biosynthesis of copper‐dependent enzymes and maintain copper levels within the range necessary to meet metabolic demands and avoid toxicity. Cu‐ATPases are the key components of sophisticated cellular machinery that evolved to provide precise inter‐ and intracellular distribution of metals, and the function of these transporters is tightly regulated. Copper along with a growing number of cytosolic proteins controls the activity, stability, and localization of Cu‐ATPases ; this regulation ensures balance between the delivery of copper to metalloenzymes in various cell compartments and copper export. Inactivating mutations in human Cu‐ ATPases ATP7A and ATP7B are associated with debilitating and often lethal disorders (Menkes disease and Wilson's disease, respectively). Biochemical and biophysical studies of ATP7A and ATP7B revealed multiple metal‐binding sites, complex multi‐domain architecture, and a significant role of interdomain interactions in the function and regulation of these transporters. This article summarizes the current data on the structure and mechanism of human Cu‐ ATPases ATP7A and ATP7B , as well as the biochemical basis of their regulation.

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

Cited by 58 publications

References 62 publications

Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Molecular Genetics of Wilson Disease

Copper TransportingATPases in Mammalian Cells

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