Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1
(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)
- author
- organization
- publishing date
- 2023-10-05
- 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}}, }