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Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria

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Lennartz, Frank ; Adams, Yvonne ; Bengtsson, Anja ; Olsen, Rebecca W ; Turner, Louise ; Ndam, Nicaise T ; Ecklu-Mensah, Gertrude ; Moussiliou, Azizath ; Ofori, Michael F ; Gamain, Benoit ; Lusingu, John P ; Petersen, Jens E V ; Wang, Christian W ; Nunes-Silva, Sofia ; Jespersen, Jakob S ; Lau, Clinton K Y ; Theander, Thor G ; Lavstsen, Thomas ; Hviid, Lars ; Higgins, Matthew K ; Jensen, Anja T R. / Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria. In: Cell Host and Microbe. 2017 ; Vol. 21, No. 3. pp. 403-414.

Bibtex

@article{f72d910a49bf49dba4e9ca07bf4e44f1,
title = "Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria",
abstract = "Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria.",
keywords = "Antigens, CD, Cell Adhesion, Computational Biology, Crystallography, X-Ray, Endothelial Protein C Receptor, Genome, Protozoan, Intercellular Adhesion Molecule-1, Malaria, Cerebral, Malaria, Falciparum, Plasmodium falciparum, Protein Binding, Protozoan Proteins, Receptors, Cell Surface, Scattering, Small Angle, Sequence Analysis, DNA, Surface Plasmon Resonance, Virulence Factors, Journal Article",
author = "Frank Lennartz and Yvonne Adams and Anja Bengtsson and Olsen, {Rebecca W} and Louise Turner and Ndam, {Nicaise T} and Gertrude Ecklu-Mensah and Azizath Moussiliou and Ofori, {Michael F} and Benoit Gamain and Lusingu, {John P} and Petersen, {Jens E V} and Wang, {Christian W} and Sofia Nunes-Silva and Jespersen, {Jakob S} and Lau, {Clinton K Y} and Theander, {Thor G} and Thomas Lavstsen and Lars Hviid and Higgins, {Matthew K} and Jensen, {Anja T R}",
note = "Copyright {\circledC} 2017 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2017",
month = "3",
day = "8",
doi = "10.1016/j.chom.2017.02.009",
language = "English",
volume = "21",
pages = "403--414",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "3",

}

RIS

TY - JOUR

T1 - Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria

AU - Lennartz, Frank

AU - Adams, Yvonne

AU - Bengtsson, Anja

AU - Olsen, Rebecca W

AU - Turner, Louise

AU - Ndam, Nicaise T

AU - Ecklu-Mensah, Gertrude

AU - Moussiliou, Azizath

AU - Ofori, Michael F

AU - Gamain, Benoit

AU - Lusingu, John P

AU - Petersen, Jens E V

AU - Wang, Christian W

AU - Nunes-Silva, Sofia

AU - Jespersen, Jakob S

AU - Lau, Clinton K Y

AU - Theander, Thor G

AU - Lavstsen, Thomas

AU - Hviid, Lars

AU - Higgins, Matthew K

AU - Jensen, Anja T R

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2017/3/8

Y1 - 2017/3/8

N2 - Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria.

AB - Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria.

KW - Antigens, CD

KW - Cell Adhesion

KW - Computational Biology

KW - Crystallography, X-Ray

KW - Endothelial Protein C Receptor

KW - Genome, Protozoan

KW - Intercellular Adhesion Molecule-1

KW - Malaria, Cerebral

KW - Malaria, Falciparum

KW - Plasmodium falciparum

KW - Protein Binding

KW - Protozoan Proteins

KW - Receptors, Cell Surface

KW - Scattering, Small Angle

KW - Sequence Analysis, DNA

KW - Surface Plasmon Resonance

KW - Virulence Factors

KW - Journal Article

U2 - 10.1016/j.chom.2017.02.009

DO - 10.1016/j.chom.2017.02.009

M3 - Journal article

VL - 21

SP - 403

EP - 414

JO - Cell Host and Microbe

JF - Cell Host and Microbe

SN - 1931-3128

IS - 3

ER -

ID: 52710072