TY - JOUR
T1 - Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1
AU - Rajan Raghavan, Sai Sundar
AU - Turner, Louise
AU - Jensen, Rasmus W.
AU - Johansen, Nicolai Tidemand
AU - Jensen, Daniel Skjold
AU - Gourdon, Pontus
AU - Zhang, Jinqiu
AU - Wang, Yong
AU - Theander, Thor Grundtvig
AU - Wang, Kaituo
AU - Lavstsen, Thomas
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1016/j.str.2023.07.011
DO - 10.1016/j.str.2023.07.011
M3 - Journal article
C2 - 37582356
AN - SCOPUS:85172200717
VL - 31
SP - 1174-1183.e4
JO - Structure
JF - Structure
SN - 0969-2126
IS - 10
ER -