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

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

doi:10.1016/j.chom.2014.11.007

Abstract

SummaryThe 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.

Highlights

Parasites, such as the Plasmodium species that cause malaria, have developed strategies to aid survival in a mammalian host and to multiply in the nutrient-rich blood
The PfEMP1 family of surface proteins is central for Plasmodium falciparum virulence and must retain the ability to bind to host receptors while diversifying to aid immune evasion
Using peptides corresponding to the endothelial protein C receptor (EPCR)-binding region, antibodies can be purified from individuals in malaria-endemic regions that block EPCR binding of diverse CIDRa1 variants

Summary

Introduction

Parasites, such as the Plasmodium species that cause malaria, have developed strategies to aid survival in a mammalian host and to multiply in the nutrient-rich blood. They must make specific interactions with host molecules, enabling them to invade cells, acquire nutrients, and populate protected environments. A common evolutionary strategy, employed by many unicellular eukaryotic parasites, is expansive development of a family of surface proteins, which lie at the interface between host and parasite. Expression switching between family members allows parasites to display a series of antigenically distinct surfaces, posing challenges for the immune system and for rational development of vaccines

Results

Discussion

Conclusion