How do malaria infected erythrocytes bind to EPCR?

Our first molecular view of how a PfEMP1 protein recognises its protein ligand

The PfEMP1 proteins of Plasmodium falciparum are found on the surfaces of infected red blood cells, where they adhere to human blood vessel and tissue surfaces, securing the infected cell from clearance and destruction by the spleen. In a previous study, our colleagues at the University of Copenhagen (Turner et al, 2013) found that parasites which produce PfEMP1 proteins that bind to the human receptor EPCR are more commonly found in cases of severe childhood malaria.

Working with Thomas Lavstsen and colleagues we took a panel of PfEMP1 domains and determined which bound to EPCR. This allowed a detailed sequence analysis of the EPCR-binders. Surprisingly we could not identify a clear sequence motif to distinguish an EPCR-binder from a non-binder. Would structural biology help?

Two structures solved by Clinton Lau revealed how PfEMP1 domains bind to EPCR, showing a hydrophobic protrusion surrounded by a hydrophilic surface. Mapping of the sequences of EPCR-binding PfEMP1 domains onto the structure showed that, while there was no sequence conservation in the binding residues, there was conservation of the shape and chemistry. 

The structure also provided insight into how the binding of infected erythrocytes to EPCR might associate with severe malaria. The PfEMP1 domain binds to the same site on EPCR as the natural ligands of this human receptor. This is a winning strategy for the parasite as it targets a location on the human receptor which cannot vary without losing its function. But it is bad for the host as adhesion blocks the natural function of EPCR, leading to damage to the tissue and to inflammation.

This study therefore shows how a parasite protein varies to evade immune detection while retaining a binding site of conserved shape and chemistry and while targeting an invariant surface of a human receptor.

Lau, C.K.Y, Turner, L., Jespersen, J.S., Lowe, E.D., Petersen, B., Wang, C.W., Petersen, J.E.V., Lusingu, J., Theander, T.G., Lavstsen, T.* and Higgins, M.K.* (2015) Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe childhood malaria. Cell Host and Microbe 17 118-129 (* joint corresponding).