Modifications in the CD36 binding domain of the Plasmodium falciparum variant antigen are responsible for the inability of chondroitin sulfate A adherent parasites to bind CD36

Adhesion of mature Plasmodium falciparum parasitized erythrocytes to microv ascular endothelial cells or to placenta contributes directly to the virule nce and severe pathology of P falciparum malaria. Whereas CD36 is the major endothelial receptor for microvasculature sequestration, infected erythroc ytes adhering in the placenta bind chondroitin sulfate A (CSA) but not CD36 . Binding to both receptors is mediated by different members of the large a nd diverse protein family P falciparum erythrocyte membrane protein-1 (PfEM P-1) and involves different regions of the molecule. The PfEMP-1-binding do main for CD36 resides in the cysteine-rich interdomain region 1 (CIDR-1). T o explore why CSA-binding parasites do not bind CD36, CIDR-1 domains from C D36- or CSA-binding parasites were expressed in mammalian cells and tested for adhesion. Although CIDR-1 domains from CD36-adherent strains strongly b ound CD36, those from CSA-adherent parasites did not. The CIDR-1 domain has also been reported to bind CSA. However, none of the CIDR-1 domains tested bound CSA. Chimeric proteins between CIDR-1 domains that bind or do not bi nd CD36 and mutagenesis experiments revealed that modifications in the mini mal CD36-binding region (M2 region) are responsible for the inability of CS A-selected parasites to bind CD36. One of these modifications, mapped to a 3-amino acid substitution in the M2 region, ablated binding in one variant and largely reduced binding of another. These findings provide a molecular explanation for the inability of placental sequestered parasites to bind CD 36 and provide additional insight into critical residues for the CIDR-1/CD3 6 interaction. (Blood. 2001;97:3268-3274) (C) 2001 by The American Society of Hematology.