Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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 LU ; Zhang, Jinqiu ; Wang, Yong ; Theander, Thor Grundtvig and Wang, Kaituo , et al. (2023) In Structure 31(10). p.4-1183
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Structure
volume
31
issue
10
pages
4 - 1183
publisher
Cell Press
external identifiers
  • pmid:37582356
  • scopus:85172200717
ISSN
0969-2126
DOI
10.1016/j.str.2023.07.011
language
English
LU publication?
yes
id
209e485f-e9e0-4ba0-bf39-86464c91007c
date added to LUP
2023-12-07 10:10:21
date last changed
2024-04-20 04:38:34
@article{209e485f-e9e0-4ba0-bf39-86464c91007c,
  abstract     = {{<p>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.</p>}},
  author       = {{Rajan Raghavan, Sai Sundar and Turner, Louise and Jensen, Rasmus W. and Johansen, Nicolai Tidemand and Jensen, Daniel Skjold and Gourdon, Pontus and Zhang, Jinqiu and Wang, Yong and Theander, Thor Grundtvig and Wang, Kaituo and Lavstsen, Thomas}},
  issn         = {{0969-2126}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{10}},
  pages        = {{4--1183}},
  publisher    = {{Cell Press}},
  series       = {{Structure}},
  title        = {{Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1}},
  url          = {{http://dx.doi.org/10.1016/j.str.2023.07.011}},
  doi          = {{10.1016/j.str.2023.07.011}},
  volume       = {{31}},
  year         = {{2023}},
}