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

Lennartz, Frank, Smith, Cameron, Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164 and Higgins, Matthew K. (2019) 'Structural insights into diverse modes of ICAM-1 binding by Plasmodium falciparum-infected erythrocytes'. Proceedings of the National Academy of Sciences, Vol 116, Issue 40, pp. 20124-20134.

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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 parasitaemia by reducing spleen-mediated clearance of the parasite. This adhesion is mediated by PfEMP1, a multi-variant 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 two distinct groups of PfEMP1, A-type and B or C (BC) - type. Here we present the first 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 Atype PfEMP1 bound to ICAM-1 shows that the two 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 BCtype
PfEMP1 present ICAM-1 at different angles, perhaps influencing the ability of neighbouring 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.

Item Type:	Article
Subjects:	QX Parasitology > Protozoa > QX 135 Plasmodia WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 150 Erythrocytes
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1073/pnas.1911900116
Depositing User:	Cathy Waldron
Date Deposited:	18 Sep 2019 08:45
Last Modified:	04 Oct 2019 14:55
URI:	https://archive.lstmed.ac.uk/id/eprint/11559

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