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. 1999 Oct 26;96(22):12333-8.
doi: 10.1073/pnas.96.22.12333.

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

S Hirotsu  1 , Y Abe, K Okada, N Nagahara, H Hori, T Nishino, T Hakoshima
Affiliations

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

S Hirotsu et al. Proc Natl Acad Sci U S A. .

Abstract

Heme-binding protein 23 kDa (HBP23), a rat isoform of human proliferation-associated gene product (PAG), is a member of the peroxiredoxin family of peroxidases, having two conserved cysteine residues. Recent biochemical studies have shown that HBP23/PAG is an oxidative stress-induced and proliferation-coupled multifunctional protein that exhibits specific bindings to c-Abl protein tyrosine kinase and heme, as well as a peroxidase activity. A 2.6-A resolution crystal structure of rat HBP23 in oxidized form revealed an unusual dimer structure in which the active residue Cys-52 forms a disulfide 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. Thus, the unusual cysteine disulfide bond is involved in peroxidation catalysis by using thioredoxin as the source of reducing equivalents. The structure also provides a clue to possible interaction surfaces for c-Abl and heme. Several significant structural differences have been found from a 1-Cys peroxiredoxin, ORF6, which lacks the C-terminal conserved cysteine corresponding to Cys-173 of HBP23.

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Figures

Figure 1
Figure 1
Overall structure and secondary structural elements of HBP23. (A) A ribbon representation of HBP23 showing the secondary structural elements. The α-helices in light blue and β-strands in pale pink form a thioredoxin fold. The other α-helices and β-strands are shown in blue and purple, respectively. The side chains of Cys-52 and Cys-173 are shown with ball-and-stick models. (B) A view along the 2-fold axis of the ribbon representation of the HBP23 dimer. The secondary structural elements of Molecule A are shown in red (α-helices) and pale pink (β-strands) and those of Molecule B in blue (α-helices) and sky blue (β-strands). Loop regions of Molecule B are in dark gray. The side chains of two cysteine residues (Cys-52 and Cys-173) at the active site are indicated by ball-and-stick models. (C) The secondary structure elements and sequence alignment of HBP23 and the related Prxs. The secondary structural elements of HBP23 and ORF6 are shown (Top and Bottom, respectively), with the same color codes as in A. For the homologues of 2-Cys Prxs (PAG, natural killer cell-enhancing factor A, and mouse macrophage stress protein), substituted residues are shown. Identical residues between HBP23 and ORF6 are highlighted in yellow.
Figure 2
Figure 2
Structural comparison between HBP23 and ORF6. HBP23 dimer (Left) and ORF6 dimer (Right) with regions displaying larger displacements highlighted with colors; green for α2 region, red for α3-α3′ region, blue for loop α4- β6, purple for loopβ7-α5, and light blue for the C-terminal tail. The C-terminal subdomain of ORF6 is colored dark yellow. Side chains of two active cysteines (Cys-52 and Cys-173), surface aromatic residues (tryptophan, phenylalanine, histidine), and proline residues are shown.
Figure 3
Figure 3
The active site of HBP23. (A) A stereo view of the active site of HBP23. Side chains of Cys-52, Cys-173, and their neighboring residues are shown. Loops are colored as in Fig. 2. (B) The accessible molecular surface around the disulfide bond between Cys-52 and Cys-173 at the active site. Cys-173 is represented with a stick model, but Cys-52 is buried inside the molecule. (C) A closeup view of the side-chain interactions of the charged residues and a putative Cl− ion at the bottom of the active site of HBP23. A water molecule contacting the Cl− ion is observed in Molecule A but is missing in Molecule B.
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