The molecular mechanism of cytoadherence to placenta or tumor cells through VAR2CSA from Plasmodium falciparum

Pregnancy Associated Malaria (PAM) threatens more than one million pregnant women and their infants in endemic regions due to poor outcomes. VAR2CSA plays a vital role in the cytoadherence of infected erythrocytes (IEs) to placenta against immuno-clearance via binding to Chondroitin sulfate A (CSA), which is displayed mostly on the surface of placental or tumor cells. In this study, we determined the cryo-EM structures of VAR2CSA ectodomain and its complex with CSA at a resolution of 3.6 Å and 3.4 Å, respectively and revealed that CSA binding induces significant conformational change for ligand accommodation. Beyond structural studies, we generated VAR2CSA fragments and mutation and evaluated their binding activity to either isolated CSA or placental and tumor cell line using multi-disciplinary techniques. The results showed that 9-site mutation in DBL2X abolished the CSA binding activity and also disrupted its binding to both placental and tumor cells. Overall, our work clearly elucidated the molecular mechanism of cytoadherence to placental or tumor cells through VAR2CSA. Which may facilitate new PAM vaccine development and improve the drug delivery systems targeting both placenta and tumors.