Solution structure of Escherichia coli glutaredoxin-2 shows similarity to mammalian glutathione-S-transferases

Glutaredoxin 2 (Grx2) from Escherichia coli is distinguished from other glu taredoxins by its larger size, low overall sequence identity and lack of el ectron donor activity with ribonucleotide reductase. However, catalysis of glutathione (GSH)-dependent general disulfide reduction by Grx2 is extremel y efficient. The high-resolution solution structure of E. coli Grx2 shows a two-domain protein, with residues 1 to 72 forming a classical "thioredoxin -fold" glutaredoxin domain, connected by an 11 residue linker to the highly helical C-terminal domain, residues 84 to 215. The active site, Cys9-Pro10 -Tyr111-Cys12, is buried in the interface between the two domains, but Cys9 is solvent-accessible, consistent with its role in catalysis. The structur es reveal the hither to unknown fact that Grx2 is structurally similar to g lutathione-S-transferases (GST), although there is no obvious sequence homo logy. The similarity of these structures gives important insights into the functional significance of a new class of mammalian GST-like proteins, the single-cysteine omega class, which have glutaredoxin oxidoreductase activit y rather than GSH-S-transferase conjugating activity. E. coli Grx 2 is stru cturally and functionally a member of this new expanding family of large gl utaredoxins. The primary function of Grx2 as a GST-like glutaredoxin is to catalyze reversible glutathionylation of proteins with GSH in cellular redo x regulation including stress responses. (C) 2001 Academic Press.