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Lau, Clinton K.Y.; Turner, Louise; Jespersen, Jakob S.; Lowe, Edward D.; Petersen, Bent; Wang, Christian W.; Petersen, Jens E.V.; Lusingu, John; Theander, Thor G.; Lavstsen, Thomas; Higgins, Matthew K.
Cell host & microbe, 01/2015, Volume: 17, Issue: 1Journal Article
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. Display omitted •EPCR binding is retained by PfEMP1 CIDRα1 domains despite huge sequence variation•Diverse CIDRα1 domains retain structural and chemical features to bind to EPCR•CIDRα1 domains mimic features of a natural ligand of EPCR and block its binding•Patient sera contain neutralizing antibodies that prevent parasite binding to EPCR PfEMP1 proteins of Plasmodium must retain binding to host receptor EPCR while diversifying for immune evasion. Using structural studies, Lau et al. show that EPCR-binding surfaces of PfEMP1 are conserved in shape and bonding potential, despite sequence diversity, and identify features that should be mimicked in immunogens preventing EPCR binding.
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