Scientific Publications by FDA Staff

Int J Parasitol 2006 Aug;36(9):1037-48

Protein disulfide isomerase assisted protein folding in malaria parasites.

Mahajan B, Noiva R, Yadava A, Zheng H, Majam V, Mohan KV, Moch JK, Haynes JD, Nakhasi H, Kumar S

Kumar S, US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Rockville, MD 20895 USA US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Rockville, MD 20895 USA Univ S Dakota, Sch Med, Div Basic Biomed Sci, Vermillion, SD 57069 USA Walter Reed Army Inst Res, Dept Immunol, Silver Spring, MD 20910 USA

In eukaryotes, the formation of protein disulfide bonds among cysteine residues is mediated by protein disulfide isomerases and occurs in the highly oxidised environment of the endoplasmic reticulum. This process is poorly understood in malaria parasites. In this paper, we report the gene isolation, sequence and phylogenetic comparisons, protein structure and thioredoxin-domain analyses of nine protein disulfide isomerases-like molecules from five species of malaria parasites including Plasmodium falciparum and Plasmodium vivax (human), Plasmodium knowlesi (simian) and Plasmodium berghei and Plasmodium yoelii (murine). Four of the studied protein disulfide isomerases belong to P. falciparum malaria and have been named PfPDI-8, PfPDI-9, PfPDI-11 and PfPDI-14, based on their chromosomal location. Among these, PfPDI-8 bears the closest similarity to a prototype PDI molecule with two thioredoxin domains (containing CGHC active sites) and a C-terminal Endoplasmic reticulum retrieval signal, SEEL. PfPDI-8 is expressed during all stages of parasite life cycle and is highly conserved (82-96% identity at amino acid level) in the other four Plasmodium species studied. Detailed biochemical analysis of PfPDI-8 revealed that this molecule is a potent oxido-reductase enzyme that facilitated the disulfide-dependent conformational folding of EBA-175, a leading malaria vaccine candidate. These studies open the avenues to understand the process of protein folding and secretory pathway in malaria parasites that in turn might aid in the production of superior recombinant vaccines and provide novel drug targets.