Abstract
The human malaria parasite, Plasmodium falciparum, is able to evade spleen-mediated clearing from blood stream by sequestering in peripheral organs. This is due to the adhesive properties conferred by the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family exported by the parasite to the surface of infected erythrocytes. Expression of the VAR2CSA variant of PfEMP1 leads to pregnancy-associated malaria, which occurs when infected erythrocytes massively sequester in the placenta by binding to low-sulfated Chondroitin Sulfate A (CSA) present in the intervillous spaces. VAR2CSA is a 350 kDa protein that carries six Duffy-Binding Like (DBL) domains, one Cysteine-rich Inter-Domain Regions (CIDR) and several inter-domain regions. In the present paper, we report for the first time the crystal structure at 2.9 Å of a VAR2CSA double domain, DBL3X-DBL4ε, from the FCR3 strain. DBL3X and DBL4ε share a large contact interface formed by residues that are invariant or highly conserved in VAR2CSA variants, which suggests that these two central DBL domains (DBL3X-DBL4ε) contribute significantly to the structuring of the functional VAR2CSA extracellular region. We have also examined the antigenicity of peptides corresponding to exposed loop regions of the DBL4ε structure.
Highlights
Ramachandran plot: most favoured allowed outliers is polymorphic, women become immune to placental infections after one or more pregnancies by the acquisition of a protective humoral response in which antibodies that block CSA binding play a dominant role[9,10,11,12]
The double domain forms a compact structure with a short linker of ten residues, K1583 to K1592 region connecting the two Duffy-binding like (DBL) modules (Fig. 1)
Contacts between the DBL3X and DBL4ε domains in the crystal structure are made essentially by invariant or highly conserved residues (Fig. 2, Table S1), suggesting that these contacts occur in the full-length VAR2CSA and contribute to its compact organization[19,20]
Summary
Ramachandran plot: most favoured allowed outliers is polymorphic, women become immune to placental infections after one or more pregnancies by the acquisition of a protective humoral response in which antibodies that block CSA binding play a dominant role[9,10,11,12]. Analysis of the full-length VAR2CSA protein by small angle X-ray scattering (SAXS) demonstrated that it has a compact structure, probably due to well-defined interdomain interactions This structural organization may be necessary to form the high-affinity, CSA-specific binding site, to which several domains contribute directly. Since an important component of immune protection against placental PEs arises from blocking adhesion to CSA, defining the binding site in atomic detail should contribute to optimization of vaccines based on VAR2CSA. This can be achieved by determining the crystal structures of individual or multiple domains. With the support of the DBL4ε structure, we have examined the antigenicity of a number of loop regions of the domain and analyzed the results in the light of other studies
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