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

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 CIDRa1 domains interact with the adjacent DBLa1 domain through central, conserved residues of the EPCR-binding site to adopt a compact conformation. Upon EPCR binding, the DBLa1 domain is displaced, and the EPCR-binding helix of CIDRa1 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.

Automated summary

Using Cryo-EM and PfEMP1 sequence diversity analysis, it was found that the CIDRa1 domains of group A PfEMP1 interact with the adjacent DBLa1 domain through central, conserved residues of the EPCR-binding site to form a compact conformation. Upon EPCR binding, the DBLa1 domain is displaced, and the EPCR-binding helix of CIDRa1 undergoes a rearrangement to reach a stable EPCR-bound conformation. This may represent a conformational masking mechanism for immune evasion in the PfEMP1 family.