Functional studies on the Wilson copper P-type ATPase and toxic milk mouse mutant.
The Wilson protein (WND; ATP7B) is an essential component of copper homeostasis. Mutations in the ATP7B gene result in Wilson disease, which is characterised by hepatotoxicity and neurological disturbances. In this paper, we provide the first direct biochemical evidence that the WND protein functions as a copper-translocating P-type ATPase in mammalian cells. Importantly, we have shown that the mutation of the conserved Met1386 to Val, in the Atp7B for the mouse model of Wilson disease, toxic milk (tx), caused a loss of Cu-translocating activity. These investigations provide strong evidence that the toxic milk mouse is a valid model for Wilson disease and demonstrate a link between the loss of catalytic function of WND and the Wilson disease phenotype.
Voskoboinik
I
I
Department of Genetics, University of Melbourne, Parkville, Victoria, 3010, Australia.
Greenough
M
M
La Fontaine
S
S
Mercer
J F
JF
Camakaris
J
J
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D006224:Cricetinae; D004274:DNA, Recombinant / Q000235:genetics; D007700:Kinetics; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D013997:Time Factors; D014162:Transfection; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D004274:DNA, Recombinant; D014638:Vanadates; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases