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Conserved residues modulate copper release in human copper chaperone Atox1
Umeå University, Faculty of Science and Technology, Chemistry.
2008 (English)In: Proceedings of the National Academy of Sciences of the United States of America PNAS, Vol. 105, no 32, 11158-63 p.Article in journal (Refereed) Published
Abstract [en]

It is unclear how the human copper (Cu) chaperone Atox1 delivers Cu to metal-binding domains of Wilson and Menkes disease proteins in the cytoplasm. To begin to address this problem, we have characterized Cu(I) release from wild-type Atox1 and two point mutants (Met10Ala and Lys60Ala). The dynamics of Cu(I) displacement from holo-Atox1 were measured by using the Cu(I) chelator bicinchonic acid (BCA) as a metal acceptor. BCA removes Cu(I) from Atox1 in a three-step process involving the bimolecular formation of an initial Atox1–Cu–BCA complex followed by dissociation of Atox1 and the binding of a second BCA to generate apo-Atox1 and Cu–BCA2. Both mutants lose Cu(I) more readily than wild-type Atox1 because of more rapid and facile displacement of the protein from the Atox1–Cu–BCA intermediate by the second BCA. Remarkably, Cu(I) uptake from solution by BCA is much slower than the transfer from holo-Atox1, presumably because of slow dissociation of DTT–Cu complexes. These results suggest that Cu chaperones play a key role in making Cu(I) rapidly accessible to substrates and that the activated protein–metal–chelator complex may kinetically mimic the ternary chaperone–metal–target complex involved in Cu(I) transfer in vivo.

Place, publisher, year, edition, pages
2008. Vol. 105, no 32, 11158-63 p.
URN: urn:nbn:se:umu:diva-10274DOI: doi:10.1073/pnas.0802928105OAI: diva2:149945
Available from: 2008-08-08 Created: 2008-08-08 Last updated: 2011-01-10Bibliographically approved

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