Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1

Sai Sundar Rajan Raghavan; Louise Turner; Rasmus W. Jensen; Nicolai Tidemand Johansen; Daniel Skjold Jensen; Pontus Gourdon; Jinqiu Zhang; Yong Wang; Thor Grundtvig Theander; Kaituo Wang; Thomas Lavstsen

doi:10.1016/j.str.2023.07.011

Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1

Sai Sundar Rajan Raghavan, Louise Turner, Rasmus W. Jensen, Nicolai Tidemand Johansen, Daniel Skjold Jensen, Pontus Gourdon, Jinqiu Zhang, Yong Wang, Thor Grundtvig Theander, Kaituo Wang^*, Thomas Lavstsen

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

2 Citations (Scopus)

Abstract

Severe Plasmodium falciparum malaria infections are caused by microvascular sequestration of parasites binding to the human endothelial protein C receptor (EPCR) via the multi-domain P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion ligands. Using cryogenic electron microscopy (Cryo-EM) and PfEMP1 sequence diversity analysis, we found that group A PfEMP1 CIDRα1 domains interact with the adjacent DBLα1 domain through central, conserved residues of the EPCR-binding site to adopt a compact conformation. Upon EPCR binding, the DBLα1 domain is displaced, and the EPCR-binding helix of CIDRα1 is turned, kinked, and twisted to reach a rearranged, stable EPCR-bound conformation. The unbound conformation and the required transition to the EPCR-bound conformation may represent a conformational masking mechanism of immune evasion for the PfEMP1 family.

Original language	English
Journal	Structure
Volume	31
Issue number	10
Pages (from-to)	1174-1183.e4
ISSN	0969-2126
DOIs	https://doi.org/10.1016/j.str.2023.07.011
Publication status	Published - 2023

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© 2023 Elsevier Ltd

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Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1. / Rajan Raghavan, Sai Sundar ; Turner, Louise; Jensen, Rasmus W.; Johansen, Nicolai Tidemand; Jensen, Daniel Skjold; Gourdon, Pontus; Zhang, Jinqiu; Wang, Yong; Theander, Thor Grundtvig ; Wang, Kaituo ; Lavstsen, Thomas.

In: Structure, Vol. 31, No. 10, 2023, p. 1174-1183.e4.

Research output: Contribution to journal › Journal article › Research › peer-review

Rajan Raghavan, Sai Sundar ; Turner, Louise ; Jensen, Rasmus W. ; Johansen, Nicolai Tidemand ; Jensen, Daniel Skjold ; Gourdon, Pontus ; Zhang, Jinqiu ; Wang, Yong ; Theander, Thor Grundtvig ; Wang, Kaituo ; Lavstsen, Thomas. / Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1. In: Structure. 2023 ; Vol. 31, No. 10. pp. 1174-1183.e4.

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title = "Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1",

abstract = "Severe Plasmodium falciparum malaria infections are caused by microvascular sequestration of parasites binding to the human endothelial protein C receptor (EPCR) via the multi-domain P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion ligands. Using cryogenic electron microscopy (Cryo-EM) and PfEMP1 sequence diversity analysis, we found that group A PfEMP1 CIDRα1 domains interact with the adjacent DBLα1 domain through central, conserved residues of the EPCR-binding site to adopt a compact conformation. Upon EPCR binding, the DBLα1 domain is displaced, and the EPCR-binding helix of CIDRα1 is turned, kinked, and twisted to reach a rearranged, stable EPCR-bound conformation. The unbound conformation and the required transition to the EPCR-bound conformation may represent a conformational masking mechanism of immune evasion for the PfEMP1 family.",

author = "{Rajan Raghavan}, {Sai Sundar} and Louise Turner and Jensen, {Rasmus W.} and Johansen, {Nicolai Tidemand} and Jensen, {Daniel Skjold} and Pontus Gourdon and Jinqiu Zhang and Yong Wang and Theander, {Thor Grundtvig} and Kaituo Wang and Thomas Lavstsen",

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year = "2023",

doi = "10.1016/j.str.2023.07.011",

language = "English",

volume = "31",

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T1 - Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1

AU - Rajan Raghavan, Sai Sundar

AU - Turner, Louise

AU - Jensen, Rasmus W.

AU - Johansen, Nicolai Tidemand

AU - Jensen, Daniel Skjold

AU - Gourdon, Pontus

AU - Zhang, Jinqiu

AU - Wang, Yong

AU - Theander, Thor Grundtvig

AU - Wang, Kaituo

AU - Lavstsen, Thomas

PY - 2023

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N2 - Severe Plasmodium falciparum malaria infections are caused by microvascular sequestration of parasites binding to the human endothelial protein C receptor (EPCR) via the multi-domain P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion ligands. Using cryogenic electron microscopy (Cryo-EM) and PfEMP1 sequence diversity analysis, we found that group A PfEMP1 CIDRα1 domains interact with the adjacent DBLα1 domain through central, conserved residues of the EPCR-binding site to adopt a compact conformation. Upon EPCR binding, the DBLα1 domain is displaced, and the EPCR-binding helix of CIDRα1 is turned, kinked, and twisted to reach a rearranged, stable EPCR-bound conformation. The unbound conformation and the required transition to the EPCR-bound conformation may represent a conformational masking mechanism of immune evasion for the PfEMP1 family.

AB - Severe Plasmodium falciparum malaria infections are caused by microvascular sequestration of parasites binding to the human endothelial protein C receptor (EPCR) via the multi-domain P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion ligands. Using cryogenic electron microscopy (Cryo-EM) and PfEMP1 sequence diversity analysis, we found that group A PfEMP1 CIDRα1 domains interact with the adjacent DBLα1 domain through central, conserved residues of the EPCR-binding site to adopt a compact conformation. Upon EPCR binding, the DBLα1 domain is displaced, and the EPCR-binding helix of CIDRα1 is turned, kinked, and twisted to reach a rearranged, stable EPCR-bound conformation. The unbound conformation and the required transition to the EPCR-bound conformation may represent a conformational masking mechanism of immune evasion for the PfEMP1 family.

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DO - 10.1016/j.str.2023.07.011

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C2 - 37582356

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VL - 31

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