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
B. Gamain et al., 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, BLOOD, 97(10), 2001, pp. 3268-3274
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.