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Abstract
VAR2CSA is a 350 kDa transmembrane protein and has been identified as the only gene overexpressed by Plasmodium falciparum infected erythrocytes selected to adhere to CSA. The resulting protein is the major receptor responsible for the adhesion of EI (infected erythrocytes) to the placenta. We were able to identify it by the antibodies present in the body of pregnant women infected with P. falciparum. Its extracellular part is composed of 6 known (epsilon) or unknown (x) domains, interspersed with Cysteine-rich Inter-Domain Regions (CIDR) and TM and ATS regions (Acidic Terminal Segment) including DBL3x. In fact, Duffy binding-like 3 X domain (DBL3X) is one of the six DBL domains of the variant surface antigen 2 CSA, belonging to the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family and involved in Pregnancy-associated Malaria.
Function
Pregnancy-associated malaria (PAM) is caused by Plasmodium falciparum-infected erythrocytes (IEs) accumulating in the placenta. The multi-domain antigen VAR2CSA confers specific adhesion of IEs to chondroitin sulphate A (CSA) in the placenta, it is the main function of DBL3x domain.
Disease
Relevance
Structural highlights
Overall of DBL3x
The DBL3x structure has three subdomains (using the nomenclature of ref 1).
The first subdomain (residues 1220−1292 ; yellow) lacks regular secondary structure except for a single turn of helix and is held together by two disulphide bonds between Cys1230-Cys1273 and Cys1251-Cys1264.
The second subdomain (residues 1293−1444 ; blue) contains four helices (H1-H4) connected by four loops. In helix H4, an unpaired cysteine (Cys1418) reacted with cystamine during refolding, gaining a cysteamine adduct observed in the electron density map and confirmed by MS. The C-terminal domain of this subdomain (residues 1424−1444) forms an extended structure that connects to the third subdomain. Cys1437 forms a disulfide bond with Cys1344 on helix H2.
The third subdomain (residues 1445−1580 ; red) has two long antiparallel helices, H5 (residues 1449−1476) and H6 (residues 1499−1529), that are connected to each other by a large loop (residues 1477−1498) and that make contacts with the first and the second subdomains. The C-terminal domain of this subdomain (residues 1563−1580) forms a flat structure of small helices connected by short linker regions. Subdomain 3 contains four disulfide bonds: Cys1462-Cys1546, Cys1476-Cys1501, Cys1505-Cys1574 and Cys1486-Cys1576. Near the C terminus, the bond between Cys1486 and Cys1576 was not visible and, presumably, was disordered in the crystal. In addition, nine N-terminal residues, three C-terminal residues and loop residues 1279−1285, 1327−1337, 1387−1397 and 1486−1494 were disordered and not visible in the electron density.
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