The Duffy-binding-like domain 1 of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a heparan sulfate ligand that requires 12 mers for binding

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), present on the surfaces of parasitized red blood cells (pRBC), mediates resetting, a virulent phenotype, Here, we show that pRBC specifically bind heparan sul fate (HS) and heparin onto their surfaces and that the resetting ligand PfE MP1 specifically adheres to heparin-Sepharose when extracted from the surfa ces of radioiodinated infected RBC. An analysis of the binding properties o f the different regions of PfEMP1 provides evidence that the Duffy-binding- like domain-1 (DBL-1) is the predominant ligand involved in HS and heparin binding. Soluble DBL-1 requires a minimal heparin fragment size of a 12-mer (approximate to 4 kd) for binding and is critically dependent on N-sulfati on. A 12-mer is also the minimal heparin fragment that disrupts naturally f ormed rosettes. DBL-1 binds specifically to erythrocytes and also to HS fro m endothelial cells and human aorta but not to chondroitin sulfate A, sugge sting that different PfEMP1s mediate adhesion to distinct glycosaminoglycan s in individual malaria parasites. Present data suggest that HS on endothel ial cells may also be involved in the sequestration of pRBC. Elucidation of these binding mechanisms opens up new possibilities for therapeutic strate gies targeting adhesive interactions of pRBC. (Blood. 2000;95:3594-3599) (C ) 2000 by The American Society of Hematology.