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Title: Structural characterisation of the interaction between Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and their human ligands in severe malaria
Author: Ng, Hong Kin
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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Sequestration of infected erythrocytes during P. falciparum infection can lead to severe malaria. PfEMP1 proteins are central to this process. Multimodular PfEMP1 proteins can bind to a variety of human ligands due to the presence of CIDR and DBL domains. CIDR and DBL domains are classified to three and six families respectively, with each thought to bind to unique human ligands. The interaction between PfEMP1 proteins and human ligands protects the infected erythrocytes against spleen-mediated destruction. Additionally, these PfEMP1 proteins undergo antigenic variation to evade immune surveillance. They also elicit immune suppression by binding to immunoglobulins within the circulatory system. The work described here focuses on two interactions between PfEMP1 on the infected erythrocytes and their human ligands, the first involving CD36 and CIDR1α domains and the second involving human IgM and DBL domains. I have expressed and purified recombinant proteins involved in both interactions. In this thesis, I have confirmed using a variety of biophysical methods that CIDR1α domains are able to bind CD36 in a 1:1 binding stoichiometry, and this accounts for the binding affinity of the full length protein. This interaction was not disrupted after performing deglycosylation procedures on CD36, allowing me to obtain stable complexes of these interacting partners for structural characterisation by crystallography. I have also confirmed the interaction between DBL domains and human IgM Fc region using similar biophysical methods. These experiments are important for paving the way towards further structural characterisation of these interactions that leads to sequestration.
Supervisor: Higgins, Matthew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Molecular biophysics (biochemistry)