Ana Cabrera1, Dante Neculai2, Vanessa Tran1, Thomas Lavstsen3, Louise Turner3, Kevin C Kain1,4. 1. SAR Laboratories, Sandra Rotman Centre, Toronto General Hospital-University Health Network, Ontario, Canada. 2. Department of Cell Biology, Zhejiang University, School of Basic Medical Sciences, Hangzhou, People's Republic of China. 3. Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Denmark. 4. Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of TorontoOntarioCanada.
Abstract
BACKGROUND: The interaction of Plasmodium falciparum-infected erythrocytes (IEs) with the host receptor CD36 is among the most studied host-parasite interfaces. CD36 is a scavenger receptor that binds numerous ligands including the cysteine-rich interdomain region (CIDR)α domains of the erythrocyte membrane protein 1 family (PfEMP1) expressed on the surface of IEs. CD36 is conserved across species, but orthologs display differential binding of IEs. METHODS: In this study, we exploited these differences, combined with the recent crystal structure and 3-dimensional modeling of CD36, to investigate malaria-CD36 structure-function relationships and further define IE-CD36 binding interactions. RESULTS: We show that a charged surface in the membrane-distal region of CD36 is necessary for IE binding. Moreover, IE interaction with this binding surface is influenced by additional CD36 domains, both proximal to and at a distance from this site. CONCLUSIONS: Our data indicate that subtle sequence and spatial differences in these domains modify receptor conformation and regulate the ability of CD36 to selectively interact with its diverse ligands.
BACKGROUND: The interaction of Plasmodium falciparum-infected erythrocytes (IEs) with the host receptor CD36 is among the most studied host-parasite interfaces. CD36 is a scavenger receptor that binds numerous ligands including the cysteine-rich interdomain region (CIDR)α domains of the erythrocyte membrane protein 1 family (PfEMP1) expressed on the surface of IEs. CD36 is conserved across species, but orthologs display differential binding of IEs. METHODS: In this study, we exploited these differences, combined with the recent crystal structure and 3-dimensional modeling of CD36, to investigate malaria-CD36 structure-function relationships and further define IE-CD36 binding interactions. RESULTS: We show that a charged surface in the membrane-distal region of CD36 is necessary for IE binding. Moreover, IE interaction with this binding surface is influenced by additional CD36 domains, both proximal to and at a distance from this site. CONCLUSIONS: Our data indicate that subtle sequence and spatial differences in these domains modify receptor conformation and regulate the ability of CD36 to selectively interact with its diverse ligands.
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