title: Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe childhood malaria.
abstract: The PfEMP1 family of surface proteins is central for Plasmodium falciparum virulence and must retain the ability to bind to host receptors while also diversifying to aid immune evasion. The interaction between CIDRα1 domains of PfEMP1 and endothelial protein C receptor (EPCR) is associated with severe childhood malaria. We combine crystal structures of CIDRα1:EPCR complexes with analysis of 885 CIDRα1 sequences, showing that the EPCR-binding surfaces of CIDRα1 domains are conserved in shape and bonding potential, despite dramatic sequence diversity. Additionally, these domains mimic features of the natural EPCR ligand and can block this ligand interaction. Using peptides corresponding to the EPCR-binding region, antibodies can be purified from individuals in malaria-endemic regions that block EPCR binding of diverse CIDRα1 variants. This highlights the extent to which such a surface protein family can diversify while maintaining ligand-binding capacity and identifies features that should be mimicked in immunogens to prevent EPCR binding.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU Oxford, UK.
authors.forename: Clinton K Y
authors.initials: CK
authors.lastname: Lau
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, 1017 Copenhagen, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, 1017 Copenhagen, Denmark.
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Jespersen
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU Oxford, UK.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Lowe
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
authors.forename: Bent
authors.initials: B
authors.lastname: Petersen
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, 1017 Copenhagen, Denmark.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Wang
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, 1017 Copenhagen, Denmark.
authors.forename: Jens E V
authors.initials: JE
authors.lastname: Petersen
authors.affiliation: National Institute for Medical Research, Tanga, 2448 Ocean Road, P.O. Box 9653, Dar es Salaan, Tanzania.
authors.forename: John
authors.initials: J
authors.lastname: Lusingu
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, 1017 Copenhagen, Denmark.
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, 1017 Copenhagen, Denmark. Electronic address: thomasl@sund.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU Oxford, UK. Electronic address: matthew.higgins@bioch.ox.ac.uk.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Higgins
mesh_terms: D000293:Adolescent; D000913:Antibodies, Protozoan / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D000074283:Endothelial Protein C Receptor; D005260:Female; D014644:Genetic Variation; D054884:Host-Pathogen Interactions; D006801:Humans; D008288:Malaria / Q000469:parasitology; D008297:Male; D010963:Plasmodium falciparum / Q000235:genetics / Q000302:isolation & purification; D011485:Protein Binding; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D017422:Sequence Analysis, DNA
chemical_list: D000913:Antibodies, Protozoan; D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C085731:erythrocyte membrane protein 1, Plasmodium falciparum