Plasmodium falciparum-CD36 structure-function relationships defined by ortholog scanning mutagenesis

TY - JOUR

T1 - Plasmodium falciparum-CD36 structure-function relationships defined by ortholog scanning mutagenesis

AU - Cabrera, Ana

AU - Neculai, Dante

AU - Tran, Vanessa

AU - Lavstsen, Thomas

AU - Turner, Louise

AU - Kain, Kevin C

N1 - © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

PY - 2019/2/23

Y1 - 2019/2/23

N2 - 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.

AB - 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.

U2 - 10.1093/infdis/jiy607

DO - 10.1093/infdis/jiy607

M3 - Journal article

C2 - 30335152

SN - 0022-1899

VL - 219

SP - 945

EP - 954

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 6

ER -