Crystal structures from the Plasmodium peroxiredoxins: new insights into oligomerization and product binding

Plasmodium falciparum is the protozoan parasite primarily responsible for more than one million malarial deaths, annually, and is developing resistance to current therapies. Throughout its lifespan, the parasite is subjected to oxidative attack, so Plasmodium antioxidant defences are essential for its survival and are targets for disease control.

To further understand the molecular aspects of the Plasmodium redox system, we solved 4 structures of Plasmodium peroxiredoxins (Prx). Our study has confirmed Pv Trx-Px1 to be a hydrogen peroxide (H₂O₂)-sensitive peroxiredoxin. We have identified and characterized the novel toroid octameric oligomer of Py Trx-Px1, which may be attributed to the interplay of several factors including: (1) the orientation of the conserved surface/buried arginine of the NNLA(I/L)GRS-loop; and (2) the C-terminal tail positioning (also associated with the aforementioned conserved loop) which facilitates the intermolecular hydrogen bond between dimers (in an A-C fashion). In addition, a notable feature of the disulfide bonds in some of the Prx crystal structures is discussed. Finally, insight into the latter stages of the peroxiredoxin reaction coordinate is gained. Our structure of Py Prx6 is not only in the sulfinic acid (RSO₂H) form, but it is also with glycerol bound in a way (not previously observed) indicative of product binding.

The structural characterization of Plasmodium peroxiredoxins provided herein provides insight into their oligomerization and product binding which may facilitate the targeting of these antioxidant defences. Although the structural basis for the octameric oligomerization is further understood, the results yield more questions about the biological implications of the peroxiredoxin oligomerization, as multiple toroid configurations are now known. The crystal structure depicting the product bound active site gives insight into the overoxidation of the active site and allows further characterization of the leaving group chemistry.