Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations

Oleg Dmitriev, Ruslan Tsivkovskii, Frits Abildgaard, Clinton T. Morgan, John L. Markley, Svetlana Lutsenko

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


Wilson disease protein (ATP7B) is a copper-transporting P1B-type ATPase that regulates copper homeostasis and biosynthesis of copper-containing enzymes in human tissues. Inactivation of ATP7B or related ATP7A leads to severe neurodegenerative disorders, whereas their overexpression contributes to cancer cell resistance to chemotherapeutics. Copper-transporting ATPases differ from other P-type ATPases in their topology and the sequence of their nucleotide-binding domain (N-domain). To gain insight into the structural basis of ATP7B function, we have solved the structure of the ATP7B N-domain in the presence of ATP by using heteronuclear multidimensional NMR spectroscopy. The N-domain consists of a six-stranded β-sheet with two adjacent α-helical hairpins and, unexpectedly, shows higher similarity to the bacterial K+-transporting ATPase KdpB than to the mammalian Ca 2+-ATPaSe or Na+,K+-ATPase. The common core structure of P-type ATPases is retained in the 3D fold of the N-domain; however, the nucleotide coordination environment of ATP7B within this fold is different. The residues H1069, G1099, G1101, I1102, G1149, and N1150 conserved in the P1B-ATPase subfamily contribute to ATP binding. Analysis of the frequent disease mutation H1069Q demonstrates that this mutation does not significantly affect the structure of the N-domain but prevents tight binding of ATP. The structure of the N-domain accounts for the disruptive effects of >30 known Wilson disease mutations. The unique features of the N-domain provide a structural basis for the development of specific inhibitors and regulators of ATP7B.

Original languageEnglish (US)
Pages (from-to)5302-5307
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
StatePublished - Apr 4 2006
Externally publishedYes


  • ATP7A
  • ATP7B
  • Copper
  • NMR structure
  • P-type ATPase

ASJC Scopus subject areas

  • General


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