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Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe

Clinton K Y Lau1, Louise Turner2, Jakob S Jespersen2

  • 1Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU Oxford, UK.

Cell Host & Microbe
|December 9, 2014
PubMed

Insights

Plasmodium falciparum surface proteins (PfEMP1) diversify for immune evasion but maintain EPCR binding for severe malaria. Antibodies targeting conserved EPCR-binding regions can block this interaction, offering a potential therapeutic strategy.

Area of Science:

  • Malariology
  • Structural Biology
  • Immunology

Background:

  • The Plasmodium falciparum surface protein family PfEMP1 is crucial for malaria parasite virulence.
  • PfEMP1 interaction with host endothelial protein C receptor (EPCR) is linked to severe childhood malaria.
  • PfEMP1 must balance immune evasion through diversification with essential host receptor binding.

Purpose of the Study:

  • To investigate the structural basis of CIDRα1 domains within PfEMP1 binding to EPCR.
  • To understand how sequence diversity in CIDRα1 domains affects EPCR binding and immune evasion.
  • To identify conserved features for potential therapeutic interventions against severe malaria.

Main Methods:

  • X-ray crystallography of CIDRα1:EPCR complexes.
  • Sequence analysis of 885 CIDRα1 domains.
  • Functional assays using EPCR-binding peptides and antibodies.

Main Results:

  • EPCR-binding surfaces of CIDRα1 domains show conserved shape and bonding potential despite sequence variation.
  • CIDRα1 domains mimic natural EPCR ligands and can block their interaction.
  • Antibodies from malaria-endemic individuals targeting EPCR-binding peptides block diverse PfEMP1 variants.

Conclusions:

  • PfEMP1 diversification is constrained by conserved EPCR-binding surfaces.
  • The EPCR-binding interface represents a vulnerable target for malaria control.
  • Conserved structural features can be exploited to develop broadly protective immunogens against severe malaria.

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