Crystal structure of a multifunctional 2-Cys peroxiredoxin heme-binding protein 23 kDa/proliferation-associated gene product

Heme-binding protein 23 kDa (HBP23). a rat isoform of human proliferation-a ssociated gene product (PAG), is a member of the peroxiredoxin family of pe roxidases, having two conserved cysteine residues. Recent biochemical studi es have shown that HBP23/PAG is an oxidative stress-induced and proliferati on-coupled multifunctional protein that exhibits specific bindings to c-Abl protein tyrosine kinase and heme, as well as a peroxidase activity. A 2.6- Angstrom resolution crystal structure of rat HBP23 in oxidized form reveale d an unusual dimer structure in which the active residue Cys-52 forms a dis ulfide bond with conserved Cys-173 from another subunit by C-terminal tail swapping. The active site is largely hydrophobic with partially exposed Cys -173, suggesting a reduction mechanism of oxidized HBP23 by thioredoxin. Th us, the unusual cysteine disulfide bond is involved in peroxidation catalys is by using thioredoxin as the source of reducing equivalents. The structur e also provides a clue to possible interaction surfaces for c-Abl and heme. Several significant structural differences have been found from a 1-Cys pe roxiredoxin, ORF6, which lacks the C-terminal conserved cysteine correspond ing to Cys-173 of HBP23.