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

Research output: Contribution to journal › Article › peer-review

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
Pages (from-to)	1174-1183.e4
Journal	Structure
Volume	31
Issue number	10
DOIs	https://doi.org/10.1016/j.str.2023.07.011
Publication status	Published - 2023 Oct 5

Subject classification (UKÄ)

Infectious Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.str.2023.07.011

Cite this

@article{209e485fe9e04ba0bf3986464c91007c,

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",

year = "2023",

month = oct,

day = "5",

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

language = "English",

volume = "31",

pages = "1174--1183.e4",

journal = "Structure",

issn = "0969-2126",

publisher = "Cell Press",

number = "10",

}

TY - JOUR

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 - 2023/10/5

Y1 - 2023/10/5

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.

U2 - 10.1016/j.str.2023.07.011

DO - 10.1016/j.str.2023.07.011

M3 - Article

C2 - 37582356

AN - SCOPUS:85172200717

SN - 0969-2126

VL - 31

SP - 1174-1183.e4

JO - Structure

JF - Structure

IS - 10

ER -

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

Abstract

Subject classification (UKÄ)

UN SDGs

Access to Document

Fingerprint

Cite this