LAUSR

Significance Malaria is one of the deadliest infectious diseases to affect humans, causing over 200 million cases and hundreds of thousands of deaths annually. Its fatal symptoms occur when parasites cause infected human red blood cells to stick to human tissue surfaces, blocking blood flow and causing inflammation. This stickiness is caused by parasite PfEMP1 proteins, which interact with different human receptors, such as ICAM-1. In this paper, we demonstrate how PfEMP1 proteins bind to ICAM-1. We find that this can happen in 2 different but related ways, perhaps influencing which additional receptors PfEMP1 can bind. We show how the parasite can adapt to allow it to stick tightly, while reducing the chance that it is detected and destroyed. A major determinant of pathogenicity in malaria caused by Plasmodium falciparum is the adhesion of parasite-infected erythrocytes to the vasculature or tissues of infected individuals. This occludes blood flow, leads to inflammation, and increases parasitemia by reducing spleen-mediated clearance of the parasite. This adhesion is mediated by PfEMP1, a multivariant family of around 60 proteins per parasite genome which interact with specific host receptors. One of the most common of these receptors is intracellular adhesion molecule-1 (ICAM-1), which is bound by 2 distinct groups of PfEMP1, A-type and B or C (BC)-type. Here, we present the structure of a domain from a B-type PfEMP1 bound to ICAM-1, revealing a complex binding site. Comparison with the existing structure of an A-type PfEMP1 bound to ICAM-1 shows that the 2 complexes share a globally similar architecture. However, while the A-type PfEMP1 bind ICAM-1 through a highly conserved binding surface, the BC-type PfEMP1 use a binding site that is more diverse in sequence, similar to how PfEMP1 interact with other human receptors. We also show that A- and BC-type PfEMP1 present ICAM-1 at different angles, perhaps influencing the ability of neighboring PfEMP1 domains to bind additional receptors. This illustrates the deep diversity of the PfEMP1 and demonstrates how variations in a single domain architecture can modulate binding to a specific ligand to control function and facilitate immune evasion.