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 journalJournal articleResearchpeer-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 languageEnglish
JournalStructure
Volume31
Issue number10
Pages (from-to)1174-1183.e4
ISSN0969-2126
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Ltd

Cite this