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Stability and ATP Binding of the Nucleotide-binding Domain of the Wilson Disease Protein: Effect of the Common H1069Q Mutation
Umeå University, Faculty of Science and Technology, Chemistry.
2008 (English)In: Journal of Molecular Biology, Vol. 383, no 5, 1097-111 p.Article in journal (Refereed) Published
Abstract [en]

Perturbation of the human copper-transporter Wilson disease protein (ATP7B) causes intracellular copper accumulation and severe pathology, known as Wilson disease (WD). Several WD mutations are clustered within the nucleotide-binding subdomain (N-domain), including the most common mutation, H1069Q. To gain insight into the biophysical behavior of the N-domain under normal and disease conditions, we have characterized wild-type and H1069Q recombinant N-domains in vitro and in silico. We find the mutant to have only 2-fold lower ATP affinity as compared to the wild-type N-domain. Both proteins unfold in an apparent two-state reaction at 20 °C and ATP stabilizes the folded state. The thermal unfolding reactions are irreversible and, for the same scan rate, the wild-type protein is more resistant to perturbation than the mutant. For both proteins, ATP increases the activation barrier towards thermal denaturation. Molecular dynamics simulations identify specific differences in both ATP orientation and protein structure that can explain the absence of catalytic activity for the mutant N-domain. Taken together, our results provide biophysical characteristics that may be general to N-domains in other P1B-ATPases as well as identify changes that may be responsible for the H1069Q WD phenotype in vivo.

Place, publisher, year, edition, pages
2008. Vol. 383, no 5, 1097-111 p.
Keyword [en]
copper transport, Wilson disease protein, irreversible transition, protein-ligand interaction, ATPbinding
URN: urn:nbn:se:umu:diva-10345DOI: doi:10.1016/j.jmb.2008.07.065OAI: diva2:150016
Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2010-01-12Bibliographically approved

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