Wilson disease protein (WND), also known asATP7B protein, is a copper-transportingP-type ATPase which is encoded by theATP7B gene. The ATP7B protein is located in thetrans-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 causeWilson's disease, a disease in which copper accumulates in tissues, leading toneurological orpsychiatric issues andliver diseases.
Wilson disease protein is associated withATP7Bgene, approximately 80 Kb, located on humanchromosome 13 and consists of 21 exons. The mRNA transcribed byATP7B gene has a size of 7.5 Kb, and which encodes a protein of 1465amino acids.[5]
The gene is a member of the P-type cation transportATPasefamily and encodes a protein with several membrane-spanning domains, an ATPaseconsensus sequence, a hinge domain, aphosphorylation site, and at least two putativecopper-binding sites. This protein functions as a monomer, exporting copper out of the cells, such as the efflux of hepatic copper into thebile. Alternate transcriptionalsplice variants, encoding different isoforms with distinctcellular localizations, have been characterized.[6] Wilson's disease is caused by variousmutations. One of the common mutations is single base pair mutation, H1069Q.[5]
ATP7B protein is a copper-transportingP-type ATPase, synthesized as a membrane protein of 165 KDa in humanhepatoma cell line,[5] and which is 57%homologous toMenkes disease-associated proteinATP7A.[7]
ATP7B consists of severaldomains:
The CPC motif (Cys-Pro-Cys) in transmembrane segment 6 characterizes the protein as a heavy metal transportingATPase.[8]
Thecopper 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.[8]
As aP-type ATPases, ATP7B undergoes auto-phosphorylation of a key conservedaspartic 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. Thendephosphorylation of the aspartic acid residue recovers the protein to ready for the next transport.[9]
Most of ATP7B protein is located in thetrans-Golgi network (TGN) ofhepatocytes, which is different from itshomologous protein ATP7A.[10] Small amount of ATP7B is located in thebrain.[11]
As a copper-transporting protein, one major function is delivering copper to copper dependent enzymes inGolgi apparatus (e.g.ceruloplasmin (CPN)).[10]
In the human body, theliver plays an important role in copper regulation including removal of extra copper.[10] ATP7B participates in the physiological pathway in the copper removal process in two ways: secreting copper intoplasma and excreting copper intobile.[7]
ATP7B receives copper fromcytosolic proteinantioxidant 1 copper chaperone (ATOX1).[5] 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.[12]
Several mutations in ATOX1 can block the copper pathways and causeWilson disease.[12]
ATP7B interacts withglutaredoxin-1 (GLRX). Subsequent transport is promoted through the reduction of intramoleculardisulfide bonds by GLRX catalysis.[13]
Wilson disease happens when accumulation of copper inside the liver causesmitochondrial damage and cell destruction and shows symptoms ofhepatic 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 includingkidney disease andneurological disease.[12] The major cause is the malfunction of ATP7B[12] by single base pair mutations, deletions, frame-shifts, splice errors inATP7B gene.[5]
