Var2CSA Minimal CSA Binding Region Is Located within the N-Terminal RegionReport as inadecuate

Var2CSA Minimal CSA Binding Region Is Located within the N-Terminal Region - Download this document for free, or read online. Document in PDF available to download.

Var2CSA, a key molecule linked with pregnancy-associated malaria PAM, causes sequestration of Plasmodium falciparum infected erythrocytes PEs in the placenta by adhesion to chondroitin sulfate A CSA. Var2CSA possesses a 300 kDa extracellular region composed of six Duffy-binding like DBL domains and a cysteine-rich interdomain region CIDRpam module. Although initial studies implicated several individual var2CSA DBL domains as important for adhesion of PEs to CSA, new studies revealed that these individual domains lack both the affinity and specificity displayed by the full-length extracellular region. Indeed, recent evidence suggests the presence of a single CSA-binding site formed by a higher-order domain organization rather than several independent binding sites located on the different domains. Here, we search for the minimal binding region within var2CSA that maintains high affinity and specificity for CSA binding, a characteristic feature of the full-length extracellular region. Accordingly, truncated recombinant var2CSA proteins comprising different domain combinations were expressed and their binding characteristics assessed against different sulfated glycosaminoglycans GAGs. Our results indicate that the smallest region within var2CSA with similar binding properties to those of the full-length var2CSA is DBL1X-3X. We also demonstrate that inhibitory antibodies raised in rabbit against the full-length DBL1X-6ε target principally DBL3X and, to a lesser extent, DBL5ε. Taken together, our results indicate that efforts should focus on the DBL1X-3X region for developing vaccine and therapeutic strategies aimed at combating PAM.

Author: Anand Srivastava, Stéphane Gangnard, Sébastien Dechavanne, Farroudja Amirat, Anita Lewit Bentley, Graham A. Bentley, Benoît Ga



Related documents