Cu2+-ATPases: Sequence analyses and implications in the Wilson disease

Wilson disease is an autosomal recessive disorder of copper metabolism, and the defective gene codes for a P-type Cu2+-ATPase. Sequence comparison rev ealed that the Cu2+-ATPases were very distinct from the Ca2+-, Na+-, H+-, a nd K+-ATPases, which however, shared significant similarity to each other. The major difference may be due to the difference in metal ligand preferenc e. Some novel conserved motifs in the Wilson disease protein were also iden tified, including a putative Walker A motif (GCGIGCKV, residues 1099-1106), and a Walker B motif (GDGVND, residues 1266-1271) for the cofactor ATP bin ding and hydrolysis, a unique KAPIQ motif (residues 910-914) in the transdu ction domain, and some motifs in the transmembrane segments probably for th e substrate specificity. Combining with the previous genetic and biochemica l data, some conserved residues could be assigned for possible functions. T his information should provide a guide for designing future studies of stru cture-function relationships in the Wilson disease gene. Sequence analysis is also useful in distinguishing whether the mutant residues are missense o r polymorphism, such as T977M was identified as a missense mutation because only small amino acid residues appear at this position.