Invasion of host erythrocytes is an essential stage in the life cycle of Plasmodium parasites and in development of the pathology of malaria. The stages of erythrocyte invasion, including initial contact, apical reorientation, junction formation, and active invagination, are directed by the coordinated release of specialised apical organelles and their parasite protein contents. Among these proteins, and central to invasion by all species, are two parasite protein families, the reticulocyte-binding protein homologue (RH) and the erythrocyte-binding like (EBL) proteins, that mediate host-parasite interactions. RH5 from Plasmodium falciparum (PfRH5) is the only member of either family demonstrated to be necessary for erythrocyte invasion in all tested strains, through its interaction with the erythrocyte surface protein basigin. Indeed, antibodies targeting either PfRH5 or basigin can block parasite invasion with high efficiency in vitro, making PfRH5 an excellent candidate for a vaccine to protect against the most deadly form of malaria. Here I present crystal structures of PfRH5 in complex with basigin and with two distinct inhibitory antibodies. This is the first structure of any RH protein, revealing a novel fold in which two three-helical bundles come together to form a kite-like architecture. The two immunoglobulin domains of basigin and the inhibitory antibodies bind to one tip of the kite. These findings provide the first structural insights into erythrocyte binding by the Plasmodium RH protein family and identify novel inhibitory epitopes to guide the design of a new generation of vaccines against the blood-stage parasite.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:655031 |
| Date | January 2014 |
| Creators | Wright, Katherine Elizabeth |
| Contributors | Higgins, Matthew Kenneth |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:5da6ecfc-8768-42cd-ad04-373b24fa659d |
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