Wilson disease protein



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

Gene
is_associated_with::Wilson disease protein is associated with ATP7B is_associated_with::gene,approximate 80 Kb, located on human is_associated_with::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 is_associated_with::amino acids.

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

Structure
ATP7B protein is a copper-transporting is_associated_with::P-type ATPase, synthesized as a membrane protein of 165 KDa in human is_associated_with::hepatoma cell line, and which is 57% is_associated_with::homologous to is_associated_with::menkes disease associated protein is_associated_with::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 is_associated_with::N-terminus in the is_associated_with::cytosol)
 * Eight Transmembrane segments

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

The is_associated_with::copper binding motif also shows a high affinity to other transition metal ions like 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 is_associated_with::P-type ATPases, ATP7B undergoes auto-is_associated_with::phosphorylation of a key conserved is_associated_with::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 is_associated_with::dephosphorylation of the aspartic acid residue recovers the protein to ready for the next transport.

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

In the human body, is_associated_with::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 is_associated_with::bile.

ATOX1
ATP7B receives copper from is_associated_with::cytosolic protein Antioxidant 1 copper chaperone (ATOX1). This protein targets ATP7B directly in liver in order to transport copper. is_associated_with::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 is_associated_with::Wilson disease.

GLRX
ATP7B interacts with is_associated_with::Glutaredoxin-1(GLRX). Subsequent transport is promoted through the reduction of intramolecular is_associated_with::disulphide bonds by GLRX catalysis.

Associations with Wilson disease
Wilson disease happens when accumulation of copper inside the liver causes is_associated_with::mitochondrial damage and cell destruction and shows symptoms of is_associated_with::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 disease could be various including is_associated_with::kidney disease and is_associated_with::neurological disease. The major cause is the malfunction of ATP7B by single base pair mutations, deletions, frame-shifts, splice errors in ATP7B gene.