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Plasmodium falciparum-CD36 Structure-Function Relationships Defined by Ortholog Scanning Mutagenesis

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@article{d142f01dc1bc4912a548edc8a460be69,
title = "Plasmodium falciparum-CD36 Structure-Function Relationships Defined by Ortholog Scanning Mutagenesis",
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.",
keywords = "Animals, Antigens, Protozoan/metabolism, Binding Sites, CD36 Antigens/chemistry, CHO Cells, COS Cells, Chlorocebus aethiops, Cricetulus, Erythrocytes/parasitology, Host-Parasite Interactions/genetics, Humans, Malaria, Falciparum/immunology, Mutagenesis, Plasmodium falciparum/immunology, Structure-Activity Relationship",
author = "Ana Cabrera and Dante Neculai and Vanessa Tran and Thomas Lavstsen and Louise Turner and Kain, {Kevin C}",
note = "{\circledC} The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.",
year = "2019",
month = "2",
day = "23",
doi = "10.1093/infdis/jiy607",
language = "English",
volume = "219",
pages = "945--954",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "University of Chicago Press",
number = "6",

}

RIS

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: journals.permissions@oup.com.

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.

KW - Animals

KW - Antigens, Protozoan/metabolism

KW - Binding Sites

KW - CD36 Antigens/chemistry

KW - CHO Cells

KW - COS Cells

KW - Chlorocebus aethiops

KW - Cricetulus

KW - Erythrocytes/parasitology

KW - Host-Parasite Interactions/genetics

KW - Humans

KW - Malaria, Falciparum/immunology

KW - Mutagenesis

KW - Plasmodium falciparum/immunology

KW - Structure-Activity Relationship

U2 - 10.1093/infdis/jiy607

DO - 10.1093/infdis/jiy607

M3 - Journal article

VL - 219

SP - 945

EP - 954

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

IS - 6

ER -

ID: 59239321