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Title: Structure of the PfEMP1:EPCR complex and inhibition of the interaction
Author: Lau, Clinton Kwun Yau
ISNI:       0000 0004 6063 3731
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family is central for Plasmodium falciparum infection. This family mediates interactions between the infected erythrocyte and the host endothelial surface, making it an obvious vaccine target. However this family is very diverse, with sixty different variants in the genome of each parasite. Despite the diversity within the PfEMP1 family, only around ten ligands have been identified. This suggests that there must be conservation of ligand binding amongst the sequence variety, which could be targeted in vaccine design strategies. This thesis explores this possibility, using the interaction between the CIDRa1 domain within the PfEMP1 and endothelial protein C receptor (EPCR) as an example, as this interaction has been associated with severe childhood malaria. This thesis details the solution of the first PfEMP1:ligand crystal structure. The two CIDR:EPCR complex structures show the binding surface of the CIDR domains to consist of a central hydrophobic residue which protrudes into a hydrophobic groove in EPCR, surrounded by a ring of hydrophilic residues. This surface mimics features of the natural EPCR ligand, protein C, and can block this ligand interaction. Combination of this structure with sequence data from 885 CIDRa1 domains show that the EPCR-binding surfaces of CIDRa1 domains are conserved in shape and bonding potential, despite dramatic sequence diversity. Having identified the conserved features of this interaction, three synthetic immunogens were designed to elicit cross-inhibitory antibodies against this interaction site. The work within this thesis shows for the first time how the malarial PfEMP1 proteins manage to simultaneously diverge whilst maintaining the capacity to bind to their ligand, and explores vaccine design strategies to raise a cross-inhibitory response.
Supervisor: Higgins, Matthew Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available