Structural Conservation Despite Huge Sequence Diversity Allows EPCR Binding by the PfEMP1 Family Implicated in Severe Childhood Malaria

Clinton K.Y. Lau, Louise Turner, Jakob S. Jespersen, Edward D. Lowe, Bent Petersen, Christian W. Wang, Jens E.V. Petersen, John Lusingu, Thor G. Theander, Thomas Lavstsen, Matthew K. Higgins

    Research output: Contribution to journalJournal articlepeer-review

    486 Downloads (Pure)

    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 CIDRa1 domains of PfEMP1 and endothelial protein C receptor (EPCR) is associated with severe
    childhood malaria. We combine crystal structures of CIDRa1:EPCR complexes with analysis of 885 CIDRa1 sequences, showing that the EPCR-binding surfaces of CIDRa1 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 CIDRa1 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.
    Original languageEnglish
    JournalCell Host & Microbe
    Volume17
    Issue number1
    Pages (from-to)118-129
    Number of pages12
    ISSN1931-3128
    DOIs
    Publication statusPublished - 2015

    Bibliographical note

    This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

    Fingerprint

    Dive into the research topics of 'Structural Conservation Despite Huge Sequence Diversity Allows EPCR Binding by the PfEMP1 Family Implicated in Severe Childhood Malaria'. Together they form a unique fingerprint.

    Cite this