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 rosetting, a virulent phenotype. Here, we show that pRBC specifically bind heparan sulfate (HS) and heparin onto their surfaces and that the rosetting ligand PfEMP1 specifically adheres to heparin-Sepharose when extracted from the surfaces of radioiodinated infected RBC. An analysis of the binding properties of 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 ( approximately 4 kd) for binding and is critically dependent on N-sulfation. A 12-mer is also the minimal heparin fragment that disrupts naturally formed rosettes. DBL-1 binds specifically to erythrocytes and also to HS from endothelial cells and human aorta but not to chondroitin sulfate A, suggesting that different PfEMP1s mediate adhesion to distinct glycosaminoglycans in individual malaria parasites. Present data suggest that HS on endothelial cells may also be involved in the sequestration of pRBC. Elucidation of these binding mechanisms opens up new possibilities for therapeutic strategies targeting adhesive interactions of pRBC.
Barragan
A
A
Microbiology and Tumor Biology Center, Karolinska Institutet and Swedish Institute for Infectious Disease Control, Stockholm, Sweden.
Fernandez
V
V
Chen
Q
Q
von Euler
A
A
Wahlgren
M
M
Spillmann
D
D
D000818:Animals; D000953:Antigens, Protozoan / Q000097:blood* / Q000737:chemistry / Q000302:isolation & purification; D001665:Binding Sites; D002846:Chromatography, Affinity; D004910:Erythrocyte Membrane / Q000469:parasitology* / Q000502:physiology / Q000648:ultrastructure; D006493:Heparin / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010963:Plasmodium falciparum / Q000502:physiology* / Q000648:ultrastructure; D015800:Protozoan Proteins / Q000097:blood* / Q000737:chemistry* / Q000302:isolation & purification
D000953:Antigens, Protozoan; D006493:Heparin; D006497:Heparan Sulfate; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum