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Tuning of Copper-Loop Flexibility in Bacillus subtilis CopZ Copper Chaperone: Role of Conserved Residues
Umeå University, Faculty of Science and Technology, Chemistry. (Biological Chemistry, Structural Biology)
2009 (English)In: The Journal of Physical Chemistry B, Vol. 113, no 7, 1919-32 p.Article in journal (Refereed) Published
Abstract [en]

Bacillus subtilis CopZ is a copper (Cu) chaperone that binds and delivers Cu to intracellular targets to maintain cellular Cu homeostasis. Like Cu chaperones from other organisms, including the human homologue Atox1, CopZ has the ferredoxin-like fold and binds Cu(I) via two Cys in a conserved M11X12C13X14X15C16 motif located in a solvent-exposed loop. Here, we have performed extensive molecular dynamics simulations on strategic CopZ variants to reveal structural and dynamic roles of three residues near and in the Cu loop (i.e., Met11, Ser12, and Tyr65). Met11 is conserved in all Cu chaperones, whereas Ser12 and Tyr65 are exchanged for Thr and Lys in eukaryotes like Atox1. Therefore, our simulations included apo and holo forms of Met11Ala, Ser12Ala, and Tyr65Ala, as well as Ser12Thr and Tyr65Lys, CopZ variants. We have discovered that the conserved Met is solvent exposed and important for optimal Cu-loop flexibility in the apo form of CopZ but is buried in the core and aids in packing of the fold in holo-CopZ. Ser12 and Tyr65 are important for assuring Cu-loop flexibility in the apo form; in the Cu-bound form, these residues participate in stabilizing electrostatic networks. The two eukaryotic residues tested are not good substitutes for the prokaryotic counterparts in CopZ. By comparisons to data for Atox1, we conclude that common residues (like Met) and unique residues (like Ser12 and Tyr65 in CopZ) have evolved differentially in prokaryotic and eukaryotic Cu chaperones to tune the flexibility of the Cu loop of the apo form and to provide electrostatic Cu-site stabilization of the holo form.

Place, publisher, year, edition, pages
ACS Publications , 2009. Vol. 113, no 7, 1919-32 p.
URN: urn:nbn:se:umu:diva-18283DOI: 10.1021/jp807594qOAI: diva2:158385
Available from: 2009-02-02 Created: 2009-02-02 Last updated: 2010-01-12Bibliographically approved

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