The glycophorin C N-linked glycan is a critical component of the ligand for the <i>Plasmodium falciparum</i> erythrocyte receptor BAEBL

<jats:p> <jats:italic>Plasmodium vivax</jats:italic> uses a single member of the Duffy binding-like (DBL) receptor family to invade erythrocytes and is not found in West Africa where its erythrocyte ligand, the Duffy blood group antigen, is missing. In contrast, <jats:italic>Plasmodium falciparum</jats:italic> expresses four members of the DBL family, and remarkably, single-point mutations of two of these receptors (BAEBL and JESEBL) bind to entirely different erythrocyte ligands, greatly expanding the range of erythrocytes that <jats:italic>P. falciparum</jats:italic> can invade. In this article, we describe the molecular basis of the binding specificity for one BAEBL variant (VSTK) that binds to glycophorin C. We demonstrate that soluble glycophorin C completely blocks the binding of BAEBL (VSTK) to human erythrocytes, requiring 0.7 μM for 50% inhibition, a concentration similar to that required by glycophorin A to block the binding of erythrocyte-binding antigen 175 to erythrocytes. BAEBL (VSTK) does not bind to Gerbich-negative erythrocytes that express a truncated form of glycophorin C because it lacks exon 3. The N-linked oligosaccharide of Gerbich-negative glycophorin C has a markedly different composition than the wild-type glycophorin C. Moreover, removal of the N-linked oligosaccharide from the wild-type glycophorin C eliminates its ability to inhibit binding of BAEBL (VSTK) to erythrocytes. These findings are consistent with the ligand for BAEBL (VSTK) being, in part, the N-linked oligosaccharide and suggest that single-point mutations in BAEBL allow <jats:italic>P. falciparum</jats:italic> to recognize oligosaccharides on different erythrocyte surface glycoproteins or glycolipids, greatly increasing its invasion range. </jats:p>