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

Structure. 2023 Oct 5;31(10):1174-1183.e4. doi: 10.1016/j.str.2023.07.011. Epub 2023 Aug 14.

Affiliations

¹ Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
² Section for Transport Biology, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Department of Experimental Medical Science, Lund University, Lund, Sweden; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴ The Provincial International Science and Technology Cooperation Base on Engineering Biology, International Campus of Zhejiang University, Haining, China.
⁵ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: kaituo@sund.ku.dk.
⁶ Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark. Electronic address: thomasl@sund.ku.dk.

PMID: 37582356
DOI: 10.1016/j.str.2023.07.011

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.