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Structural insights into diverse modes of ICAM-1 binding by Plasmodium falciparum -infected erythrocytes

DOI: 10.1073/pnas.1911900116 DOI Help

Authors: Frank Lennartz (University of Oxford) , Cameron Smith (University of Oxford) , Alister G. Craig (Liverpool School of Tropical Medicine) , Matthew K. Higgins (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 8

State: Published (Approved)
Published: September 2019

Open Access Open Access

Abstract: 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.

Journal Keywords: malaria; PfEMP1; ICAM-1; cytoadhesion

Subject Areas: Biology and Bio-materials

Instruments: B21-High Throughput SAXS , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography