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

DOI: 10.1016/j.chom.2014.11.007
PMID: 25482433

Authors: Clinton K. Y. Lau (University of Oxford) , Louise Turner (University of Copenhagen) , Jakob S. Jespersen (University of Copenhagen) , Edward D. Lowe (University of Oxford) , Bent Petersen (Technical University of Denmark) , Christian W. Wang (University of Copenhagen) , Jens E. V. Petersen (University of Copenhagen) , John Lusingu (National Institute for Medical Research (Tanzania)) , Thor G. Theander (University of Copenhagen) , Thomas Lavstsen (University of Copenhagen) , Matthew K. Higgins (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Host & Microbe , VOL 17 (1) , PAGES 118 - 129

State: Published (Approved)
Published: January 2015

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.

Diamond Keywords: Malaria

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 20/10/2015 15:45

Discipline Tags:

Pathogens Infectious Diseases Disease in the Developing World Health & Wellbeing Structural biology Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)