2ARF

Solution structure of the Wilson ATPase N-domain in the presence of ATP

Summary for 2ARF

• Entry DOI: 10.2210/pdb2arf/pdb
• NMR Information: BMRB: 6914
• Descriptor: WILSON DISEASE ATPASE (1 entity in total)
• Functional Keywords: atpase, wilson disease, p-type atpase, atp7b, copper transport, nucleotide binding, atp binding, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Golgi apparatus, trans-Golgi network membrane; Multi-pass membrane protein (By similarity). Isoform 2: Cytoplasm. WND/140 kDa: Mitochondrion: P35670
• Total number of polymer chains: 1
• Total formula weight: 17309.91

Authors

Dmitriev, O.,Tsivkovskii, R.,Abildgaard, F.,Morgan, C.T.,Markley, J.L.,Lutsenko, S. (deposition date: 2005-08-19, release date: 2006-02-28, Last modification date: 2024-05-22)

Primary citation

Dmitriev, O.,Tsivkovskii, R.,Abildgaard, F.,Morgan, C.T.,Markley, J.L.,Lutsenko, S.
Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations
Proc.Natl.Acad.Sci.Usa, 103:5302-5307, 2006

PubMed Abstract: Wilson disease protein (ATP7B) is a copper-transporting P(1B)-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 beta-sheet with two adjacent alpha-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 P(1B)-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.

PubMed: 16567646
DOI: 10.1073/pnas.0507416103

Experimental method

SOLUTION NMR