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 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.

Turner, LouiseCopenhagen University Hospital (author)
Jensen, Rasmus W.Copenhagen University Hospital (author)
Johansen, Nicolai TidemandUniversity of Copenhagen (author)
Jensen, Daniel SkjoldCopenhagen University Hospital (author)
Gourdon, PontusLund University,Lunds universitet,Medicinsk strukturbiologi,Forskargrupper vid Lunds universitet,Membranproteinstrukturbiologi,Medical Structural Biology,Lund University Research Groups,Membrane Protein Structural Biology,University of Copenhagen(Swepub:lu)med-pgd (author)
Zhang, JinqiuZhejiang University (author)
Wang, YongZhejiang University (author)
Theander, Thor GrundtvigCopenhagen University Hospital (author)
Wang, KaituoUniversity of Copenhagen (author)
Lavstsen, ThomasCopenhagen University Hospital (author)
Copenhagen University HospitalUniversity of Copenhagen (creator_code:org_t)

By the author/editor: Rajan Raghavan, ...; Turner, Louise; Jensen, Rasmus W ...; Johansen, Nicola ...; Jensen, Daniel S ...; Gourdon, Pontus; show more...; Zhang, Jinqiu; Wang, Yong; Theander, Thor G ...; Wang, Kaituo; Lavstsen, Thomas; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Infectious Medic ...

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