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Copper-chaperones with dicoordinated Cu(I)--unique protection mechanism.

Authors
  • Ansbacher, Tamar
  • Chourasia, Mukesh
  • Shurki, Avital
Type
Published Article
Journal
Proteins Structure Function and Bioinformatics
Publisher
Wiley (John Wiley & Sons)
Publication Date
Aug 01, 2013
Volume
81
Issue
8
Pages
1411–1419
Identifiers
DOI: 10.1002/prot.24291
PMID: 23553875
Source
Medline
Keywords
License
Unknown

Abstract

Cu(I) dicoordination with thiolate ligands is not common. Yet, different from its homologue proteins, human copper chaperone is known to bind Cu(I) using this low coordination number while binding Cu(I) only via the two conserved Cysteine residues, Cys12 and Cys15. Based on structural analysis, this work determines that the protein possesses two distinct conformations referred to as "in" and "out" due to the relative positioning of Cys12 (one of Cu(I) binding residues). The "out" conformation, with Cys12 pointing out, imposes a buried Cu(I) position, whereas the "in" conformation with Cys12 pointing inwards results in a more exposed Cu(I) thus, available for transfer. Using QM/MM methods along with thermodynamic cycles these two conformations are shown to exhibit different coordination preference, suggesting that the protein has evolved to have a unique Cu(I) protection mechanism. It is proposed that the "out" conformation with a preference to dicoordination prevents Cu(I) interaction with external ligands and/or Cu(I) release to the solvent, whereas the "in" conformation with preference to tricoordinated Cu(I), facilitates Cu(I) transfer to target proteins, where additional ligands are involved.

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