Receptor-binding residues lie in central regions of Duffy-binding-like domains involved in red cell invasion and cytoadherence by malaria parasites.
Erythrocyte invasion by malaria parasites and cytoadherence of Plasmodium falciparum-infected erythrocytes to host capillaries are 2 key pathogenic mechanisms in malaria. The receptor-binding domains of erythrocyte-binding proteins (EBPs) such as Plasmodium falciparum EBA-175, which mediate invasion, and P falciparum erythrocyte membrane protein 1 (PfEMP-1) family members, which are encoded by var genes and mediate cytoadherence, have been mapped to conserved cysteine-rich domains referred to as Duffy-binding-like (DBL) domains. Here, we have mapped regions within DBL domains from EBPs and PfEMP-1 that contain receptor-binding residues. Using biochemical and molecular methods we demonstrate that the receptor-binding residues of parasite ligands that bind sialic acid on glycophorin A for invasion as well as complement receptor-1 and chondroitin sulfate A for cytoadherence map to central regions of DBL domains. In contrast, binding to intercellular adhesion molecule 1 (ICAM-1) requires both the central and terminal regions of DBLbetaC2 domains. Determination of functional regions within DBL domains is the first step toward understanding the structure-function bases for their interaction with diverse host receptors.
Mayor
Alfredo
A
Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), PO Box 10504, Aruna Asaf Ali Marg, New Delhi 110067, India.
Bir
Nivedita
N
Sawhney
Ritica
R
Singh
Shailja
S
Pattnaik
Priyabrata
P
Singh
Saurabh Kumar
SK
Sharma
Amit
A
Chitnis
Chetan E
CE
D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002809:Chondroitin Sulfates / Q000235:genetics / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology; D006021:Glycophorins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D000953:Antigens, Protozoan; C066001:Duffy antigen binding protein, Plasmodium; D006021:Glycophorins; D008024:Ligands; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D011951:Receptors, Complement; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; C065668:erythrocyte-binding antigen 175, Plasmodium; D018799:Intercellular Adhesion Molecule-1; D002809:Chondroitin Sulfates; D019158:N-Acetylneuraminic Acid