Wilson disease protein

ATP7B
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2ROP, 2EW9, 2KOY, 2LQB
Identifiers
Aliases	ATP7B, PWD, WC1, WD, WND, ATPase copper transporting beta
External IDs	OMIM: 606882; MGI: 103297; HomoloGene: 20063; GeneCards: ATP7B; OMA:ATP7B - orthologs
Gene location (Human) Chr. Chromosome 13 (human) Band 13q14.3 Start 51,930,436 bp End 52,012,125 bp
Gene location (Mouse) Chr. Chromosome 8 (mouse) Band 8 A2|8 10.78 cM Start 22,482,801 bp End 22,550,321 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in nasal epithelium right testis left testis olfactory zone of nasal mucosa jejunal mucosa right lobe of liver germinal epithelium gonad testicle right hemisphere of cerebellum Top expressed in yolk sac pharynx gastrula lumbar subsegment of spinal cord urethra right lung right lung lobe submandibular gland left lung lobe respiratory epithelium More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding metal ion binding P-type divalent copper transporter activity ATPase-coupled cation transmembrane transporter activity protein binding copper ion binding hydrolase activity ATP binding copper ion transmembrane transporter activity Cellular component cytoplasm integral component of membrane trans-Golgi network membrane membrane Golgi membrane integral component of plasma membrane trans-Golgi network basolateral plasma membrane mitochondrion perinuclear region of cytoplasm endosome late endosome Golgi apparatus cytoplasmic vesicle Biological process protein maturation by copper ion transfer copper ion transmembrane transport metal ion transport copper ion import cation transport ion transport copper ion export ion transmembrane transport sequestering of calcium ion cellular zinc ion homeostasis cellular copper ion homeostasis lactation response to copper ion copper ion transport transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 540 11979 Ensembl ENSG00000123191 ENSMUSG00000006567 UniProt P35670 Q64446 RefSeq (mRNA) NM_000053 NM_001005918 NM_001243182 NM_001330578 NM_001330579 NM_007511 RefSeq (protein) NP_000044 NP_001005918 NP_001230111 NP_001317507 NP_001317508 NP_000044.2 NP_000044.2 NP_001005918.1 NP_001230111.1 NP_031537 NP_001390638 Location (UCSC) Chr 13: 51.93 – 52.01 Mb Chr 8: 22.48 – 22.55 Mb PubMed search
Wikidata
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Physiological pathway of copper in human body. Cu = copper, CP = ceruloplasmin, ATP7B protein is in Hepatocyte.

Simple model of structural feature of ATP7B protein. Cu=Copper binding motif

Wilson disease protein (WND), also known as ATP7B protein, is a copper-transporting P-type ATPase which is encoded by the ATP7B gene. The ATP7B protein is located in the trans-Golgi network of the liver and brain and balances the copper level in the body by excreting excess copper into bile and plasma. Genetic disorder of the ATP7B gene may cause Wilson's disease, a disease in which copper accumulates in tissues, leading to neurological or psychiatric issues and liver diseases.

Gene

Wilson disease protein is associated with ATP7B gene, approximately 80 Kb, located on human chromosome 13 and consists of 21 exons. The mRNA transcribed by ATP7B gene has a size of 7.5 Kb, and which encodes a protein of 1465 amino acids.

The gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least two putative copper-binding sites. This protein functions as a monomer, exporting copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Wilson's disease is caused by various mutations. One of the common mutations is single base pair mutation, H1069Q.

Structure

ATP7B protein is a copper-transporting P-type ATPase, synthesized as a membrane protein of 165 KDa in human hepatoma cell line, and which is 57% homologous to Menkes disease-associated protein ATP7A.

ATP7B consists of several domains:

• Phosphatase domain (TGEA motif Thr-Gly-Glu-Ala)
• Phosphorylation domain (DKTGT motif Asp-Lys-Thr-Gly-Thr)
• ATP binding domain (TGDN motif)
• Metal binding domain (six copper binding motifs at the N-terminus in the cytosol)
• Eight transmembrane segments

The CPC motif (Cys-Pro-Cys) in transmembrane segment 6 characterizes the protein as a heavy metal transporting ATPase.

The copper binding motif also shows a high affinity to other transition metal ions such as zinc Zn(II), cadmium Cd(II), gold Au(III), and mercury Hg(II). However, copper is able to decrease the zinc binding affinity at low concentration and increase copper binding affinity dramatically with increasing concentration to ensure a strong binding between the motif and copper.

As a P-type ATPases, ATP7B undergoes auto-phosphorylation of a key conserved aspartic acid (D) residue in the DKTGT motif. The ATP binding to the protein initiates the reaction and copper binds to the transmembrane region. Then phosphorylation occurs at the aspartic acid residue in the DKTGT motif with Cu release. Then dephosphorylation of the aspartic acid residue recovers the protein to ready for the next transport.

Function

Most of ATP7B protein is located in the trans-Golgi network (TGN) of hepatocytes, which is different from its homologous protein ATP7A. Small amount of ATP7B is located in the brain. As a copper-transporting protein, one major function is delivering copper to copper dependent enzymes in Golgi apparatus (e.g. holo-ceruloplasmin (CPN)).

In the human body, the liver plays an important role in copper regulation including removal of extra copper. ATP7B participates in the physiological pathway in the copper removal process in two ways: secreting copper into plasma and excreting copper into bile.

Interactions

ATOX1

ATP7B receives copper from cytosolic protein antioxidant 1 copper chaperone (ATOX1). This protein targets ATP7B directly in liver in order to transport copper. ATOX1 transfers copper from cytosol to the metal binding domain of ATP7B which control the catalytic activity of ATP7B.

Several mutations in ATOX1 can block the copper pathways and cause Wilson disease.

GLRX

ATP7B interacts with glutaredoxin-1 (GLRX). Subsequent transport is promoted through the reduction of intramolecular disulfide bonds by GLRX catalysis.

Associations with Wilson's disease

Wilson disease happens when accumulation of copper inside the liver causes mitochondrial damage and cell destruction and shows symptoms of hepatic disease. Then, the loss of excretion of copper in bile leads to an increasing concentration of copper level in urine and causes kidney problems. Therefore, symptoms of Wilson's disease could be various including kidney disease and neurological disease. The major cause is the malfunction of ATP7B by single base pair mutations, deletions, frame-shifts, splice errors in ATP7B gene.

See also

• ATP7A and Menkes disease
• ATOX1

Further reading

• Harris ED (2000). "Cellular copper transport and metabolism". Annu. Rev. Nutr. 20: 291–310. doi:10.1146/annurev.nutr.20.1.291. PMID 10940336.
• Cox DW, Moore SD (2003). "Copper transporting P-type ATPases and human disease". J. Bioenerg. Biomembr. 34 (5): 333–8. doi:10.1023/A:1021293818125. PMID 12539960. S2CID 21471699.
• Lutsenko S, Efremov RG, Tsivkovskii R, Walker JM (2003). "Human copper-transporting ATPase ATP7B (the Wilson's disease protein): biochemical properties and regulation". J. Bioenerg. Biomembr. 34 (5): 351–62. doi:10.1023/A:1021297919034. PMID 12539962. S2CID 11966711.
• Chappuis P, Bost M, Misrahi M, Duclos-Vallée JC, Woimant F (2006). "[Wilson disease: clinical and biological aspects]". Ann. Biol. Clin. (Paris). 63 (5): 457–66. PMID 16230279.
• La Fontaine S, Mercer JF (2007). "Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis". Arch. Biochem. Biophys. 463 (2): 149–67. doi:10.1016/j.abb.2007.04.021. PMID 17531189.
• Lutsenko S, LeShane ES, Shinde U (2007). "Biochemical basis of regulation of human copper-transporting ATPases". Arch. Biochem. Biophys. 463 (2): 134–48. doi:10.1016/j.abb.2007.04.013. PMC 2025638. PMID 17562324.
• Banci L, Bertini I, Cantini F, Ciofi-Baffoni S (Aug 2010). "Cellular copper distribution: a mechanistic systems biology approach". Cellular and Molecular Life Sciences. 67 (15): 2563–89. doi:10.1007/s00018-010-0330-x. PMC 11115773. PMID 20333435. S2CID 41967295.

External links

• GeneReviews/NIH/NCBI/UW entry on Wilson Disease or Hepatolenticular Degeneration
• Wilson+disease+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)