Molecular architecture and domain arrangement of the placental malaria protein VAR2CSA suggests a model for receptor binding

VAR2CSA is the placental-malaria specific member of the antigenically variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of Plasmodium falciparum infected host red blood cells and binds to specific chondroitin-4-sulfate (CSA) chains of the placental proteoglycan receptor. The functional ~310 kDa ectodomain of VAR2CSA is a multi-domain protein that requires a minimum 12-mer CSA molecule for specific, high affinity receptor binding. However, how these domains interact to create the receptor binding surface is not known, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative location of the domains creates two distinct pores that can each accommodate the 12-mer of CSA, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of IRBCs and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria.