Human copper-transporting ATPase ATP7B (the Wilson's disease protein): biochemical properties and regulation.
Wilson's disease protein (WNDP) is a product of a gene ATP7B that is mutated in patients with Wilson's disease, a severe genetic disorder with hepatic and neurological manifestations caused by accumulation of copper in the liver and brain. In a cell, WNDP transports copper across various cell membranes using energy of ATP-hydrolysis. Copper regulates WNDP at several levels, modulating its catalytic activity, posttranslational modification, and intracellular localization. This review summarizes recent studies on enzymatic function and copper-dependent regulation of WNDP. Specifically, we describe the molecular architecture and major biochemical properties of WNDP, discuss advantages of the recently developed functional expression of WNDP in insect cells, and summarize the results of the ligand-binding studies and molecular modeling experiments for the ATP-binding domain of WNDP. In addition, we speculate on how copper binding may regulate the activity and intracellular distribution of WNDP, and what role the human copper chaperone Atox1 may play in these processes.
Lutsenko
Svetlana
S
Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201, USA. lutsenko@ohsu.edu
Efremov
Roman G
RG
Tsivkovskii
Ruslan
R
Walker
Joel M
JM
D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D015971:Gene Expression Regulation, Enzymologic; D006527:Hepatolenticular Degeneration / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017433:Protein Structure, Secondary
D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases