Crystal structure of plasmoredoxin, a redox-active protein unique for malaria parasites

Karin Fritz-Wolf; Jochen Bathke; Stefan Rahlfs; Katja Becker

doi:10.1016/j.crstbi.2022.03.004

Crystal structure of plasmoredoxin, a redox-active protein unique for malaria parasites

Curr Res Struct Biol. 2022 Apr 1:4:87-95. doi: 10.1016/j.crstbi.2022.03.004. eCollection 2022.

Authors

Karin Fritz-Wolf^{1

2}, Jochen Bathke¹, Stefan Rahlfs¹, Katja Becker¹

Affiliations

¹ Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, 35392, Giessen, Germany.
² Max-Planck Institute for Medical Research, 69120, Heidelberg, Germany.

Abstract

Plasmoredoxin is a 22 kDa thiol-disulfide oxidoreductase involved in cellular redox regulatory processes and antioxidant defense. The 1.6 Å structure of the protein, solved via X-ray crystallography, adopts a modified thioredoxin fold. The structure reveals that plasmoredoxin, unique for malarial parasites, forms a new subgroup of thioredoxin-like proteins together with tryparedoxin, unique for kinetoplastids. Unlike most members of this superfamily, Plrx does not have a proline residue within the CxxC redox motif. In addition, the Plrx structure has a distinct C-terminal domain. Similar to human thioredoxin, plasmoredoxin forms monomers and dimers, which are also structurally similar to the human thioredoxin dimer, and, as in humans, plasmoredoxin is inactive as a dimer. Monomer-dimer equilibrium depends on the surrounding redox conditions, which could support the parasite in reacting to oxidative challenges. Based on structural considerations, the residues of the dimer interface are likely to interact with target proteins. In contrast to human and Plasmodium falciparum thioredoxin, however, there is a cluster of positively charged residues at the dimer interface of plasmoredoxin. These intersubunit (lysine) residues might allow binding of the protein to cellular membranes or to plasminogen. Malaria parasites lack catalase and glutathione peroxidase and therefore depend on their other glutathione and thioredoxin-dependent redox relays. Plasmoredoxin could be part of a so far unknown electron transfer system that only occurs in these parasites. Since the surface charge of plasmoredoxin differs significantly from other members of the thioredoxin superfamily, its three-dimensional structure can provide a model for designing selective redox-modulatory inhibitors.

Keywords: Antioxidants; Bacteroides fragilis, Bf; Crithidia fasciculata, Cf; Disulfide bonds; Human, h; Leishmania major, Lm; Monomer–dimer population; Plasmodium falciparum; Plasmodium falciparum, Pf; Plasmoredoxin; Redox; Thioredoxin; Trx, thioredoxin; Trypanosoma brucei, Tb; Wuchereria bancrofti, Wb; amino acids, aa; glutaredoxin, Grx; glutathione (reduced / oxidized), GSH / GSSG; glutathione reductase, GR; peroxiredoxin Prx, either 2-Cys-Prx or Prx1m; plasmoredoxin, Plrx; thioredoxin reductase, TrxR; trypanothione, Try (reduced, oxidized); tryparedoxin reductase, TR; tryparedoxin, Txn.