Abstract
AbstractBacteria possess cytosolic proteins (Csp3s) capable of binding large quantities of copper and preventing toxicity. Crystal structures of a Csp3 plus increasing amounts of CuI provide atomic‐level information about how a storage protein loads with metal ions. Many more sites are occupied than CuI equiv added, with binding by twelve central sites dominating. These can form [Cu4(S‐Cys)4] intermediates leading to [Cu4(S‐Cys)5]−, [Cu4(S‐Cys)6]2−, and [Cu4(S‐Cys)5(O‐Asn)]− clusters. Construction of the five CuI sites at the opening of the bundle lags behind the main core, and the two least accessible sites at the opposite end of the bundle are occupied last. Facile CuI cluster formation, reminiscent of that for inorganic complexes with organothiolate ligands, is largely avoided in biology but is used by proteins that store copper in the cytosol of prokaryotes and eukaryotes, where this reactivity is also key to toxicity.
Highlights
Important metabolic enzymes in eukaryotes and prokaryotes require copper for their active sites.[1]
Cu12 and Cu14 are bound by the Cys residues of CXXXC motifs, that is, from the same a-helix, whilst Cu11 and Cu13 are ligated by Cys residues on different helices (Cu13 is weakly coordinated by Asn 58)
The position of Cu11 in 2 equiv MtCsp3 corresponds to Cu11b in the 8 and 14 equiv structures, which is bound before Cu11a
Summary
Important metabolic enzymes in eukaryotes and prokaryotes require copper for their active sites.[1]. 9 equiv, CuI ions are found at 18 locations in MtCsp3 with a total occupancy of 8.2 (Figure 2 and Table S2 in the Supporting Information).
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