Mapping a common interaction site used by Plasmodium falciparum Duffy binding‐like domains to bind diverse host receptors

The Duffy binding‐like (DBL) domain is a key adhesive module in Plasmodium falciparum, present in both erythrocyte invasion ligands (EBLs) and the large and diverse P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of cytoadherence receptors. DBL domains bind a variety of different host receptors, including intercellular adhesion molecule 1 (ICAM‐1), a receptor interaction that may have a role in infected erythrocyte binding to cerebral blood vessels and cerebral malaria. In this study, we expressed the nearly full complement of DBLβ‐C2 domains from the IT4/25/5 (IT4) parasite isolate and showed that ICAM‐1‐binding domains (DBLβ‐C2ICAM‐1) were confined to group B and group C PfEMP1 proteins and were not present in group A, suggesting that ICAM‐1 selection pressure differs between PfEMP1 groups. To further dissect the molecular determinants of binding, we modelled a DBLβ‐C2ICAM‐1 domain on a solved DBL structure and created alanine substitution mutants in two DBLβ‐C2ICAM‐1 domains. This analysis indicates that the DBLβ‐C2::ICAM‐1 interaction maps to the equivalent glycan binding region of EBLs, and suggests a general model for how DBL domains evolve under dual selection for host receptor binding and immune evasion.