Molecular basis of binding of the Plasmodium falciparum receptor BAEBL to erythrocyte receptor glycophorin C

Abstract

Plasmodium falciparum invades human erythrocytes by redundant pathways. Unlike Plasmodium vivax that has one Duffy Binding-Like (DBL) receptor, P. falciparum has four members of the DBL receptor family. Furthermore, one of these DBL genes, BAEBL, has polymorphisms at four amino acids in region II; each polymorphism binds to a different erythrocyte receptor. One BAEBL variant (VSTK) binds specifically to erythrocyte glycophorin C and binds poorly to neuraminidase-treated erythrocytes. When the amino acid threonine (T121) in BAEBL (VSTK) is changed to a lysine (VSKK), it no longer requires sialic acid as a receptor. To explore the molecular basis of sialic acid binding, we modeled the structure of region II of BAEBL (VSTK) on the crystal structure of a related DBL receptor, region II of erythrocyte binding antigen-175 (EBA-175). Four charged amino acids, R52, R114, E54 and D125, are predicted to surround T121 in BAEBL (VSTK). They were individually mutated to alanine (R52A, R114A, E54A, and D125A) or lysine (R52K, R114K) and expressed on the surface of Chinese hamster ovary (CHO-K1) cells. BAEBL (VSTK) with mutations in R52 or R114 of BAEBL (VSTK) bound neuraminidase-treated erythrocytes. Unlike the arginine mutations, E54A and D125A still bound poorly to neuraminidase-treated erythrocytes. These findings suggest that the two arginine residues surrounding T121 are critical for the binding specificity of BAEBL (VSTK) to sialic acid and suggest a role for arginine in sialic acid binding independent of its negative charge.