Abstract
The human parasites Schistosoma mansoni and Leishmania major are co-endemic and a major threat to human health. Though displaying different tissue tropisms, they excrete/secrete similar subsets of intracellular proteins that, interacting with the host extracellular matrix (ECM), help the parasites invading the host. We selected one of the most abundant proteins found in the secretomes of both parasites, protein disulfide isomerase (PDI), and performed a comparative screening with surface plasmon resonance imaging (SPRi), looking for ECM binding partners. Both PDIs bind heparan sulfate; none of them binds collagens; each of them binds further ECM components, possibly linked to the different tropisms. We investigated by small-angle X-ray scattering both PDIs structures and those of a few complexes with host partners, in order to better understand the differences within this conserved family fold. Furthermore, we highlighted a previously undisclosed moonlighting behaviour of both PDIs, namely a concentration-dependent switch of function from thiol-oxidoreductase to holdase. Finally, we have tried to exploit the differences to look for possible compounds able to interfere with the redox activity of both PDI.
Highlights
Vector borne diseases are major threats to human health worldwide[1]
The genes encoding L. major PDI (LmPDI) and SmERp60 were cloned, the corresponding proteins were expressed in E. coli and purified to homogeneity by affinity chromatography, as reported in the Methods section
The content of beta strands and coiled portions computed from the CD spectra was in line with that inferred from HsPDIA3/ERp57 crystal structure (PDB 3F8U33); there was a higher content of alpha helix in LmPDI with respect to SmErp[60] and HsPDIA3/ERp57 (Table 1), making it more similar to the secondary structure content of the yeast homologue Saccharomyces cerevisiae PDI (ScPDI) (Table 1) computed from the crystal structure (PDB 2B5E31)
Summary
Vector borne diseases (including malaria, Dengue, human trypanosomiasis, leishmaniasis, schistosomiasis and Chagas disease) are major threats to human health worldwide[1]. Www.nature.com/scientificreports containing between 2 and 4 Trx-like domains[16,17] They catalyse the oxidation and/or shuffling of disulphides in substrate proteins and are involved in oxidative folding, mediated by their disulphide bond of high reduction potential and a thiol group of low pKa. The active site is composed of a CXXC motif and by a cleft capable to host a variety of large peptidyl substrates[16,17]. PDIs from pathogens have recently come centre stage for their “Janus” behaviour[18] These proteins can exist in two forms: a cytosolic/ER one and a tegument/extracellular one, independently of the presence of a signal peptide for secretion. They act intracellularly as oxidative chaperones, but when secreted by the parasites they interact with host proteins, possibly modulating the host response. Sometimes they are helped by the host PDI as documented for L. chagasi and Dengue virus[19,20]
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