Keele Research Repository

This thesis describes biochemical and biophysical studies of two protein domains that are believed to be involved in the interaction between the merozoites of Plasmodium falciparum and human red blood cells. The parasite protein fragment derives from the erythrocyte binding antigen 181 (EBA-181) invasion protein, and the human protein fragment comes from the 4.1R erythrocyte skeletal protein. The initial goal of the PhD project was to derive structural information on the nature of this complex, with a perspective towards generating new therapeutic approaches.

Extensive biochemical and biophysical characterisation of the complex was carried out and is described in detail in Chapter 3 of the thesis: the results confirm the interaction, add insights to the stability of the complex and suggest the presence of significant disorder in both the individual proteins and the complex. Structural studies were carried out using small-angle neutron and X-ray scattering, used in conjunction with selective deuteration. These studies, which are described in Chapter 4, provide low resolution images of the individual proteins and of the complex; these have been compared to structure predictions using bioinformatics. In Chapter 5, solution state NMR studies were carried out, principally on the EBA-181 protein, but with preliminary results from titration work designed to further probe the nature of the interaction between the two proteins. Chapter 6 concludes the thesis with a summary of the work placed in context of the host-pathogen interaction, and proposes directions for future work.