Structural and functional dissection of the RH5:CyRPA:RIPR complex required for erythrocyte invasion by Plasmodium falciparum (360G-Wellcome-101020_Z_13_A)
Invasion of human erythrocytes by Plasmodium falciparum is essential for parasite replication and occurs before the symptoms of malaria. It is a complex process involving many parasite surface proteins. Recently, one of these, RH5, emerged as the leading vaccine candidate to target the ‘blood stage’ of the parasite life cycle. RH5 interacts with erythrocyte basigin while monoclonal antibodies that prevent binding also prevent erythrocyte invasion. Immunization with RH5 protects animal models from parasite infection and RH5 enters human clinical trials in 2016. We already determined the structure of RH5 bound to basigin and inhibitory antibodies: a major goal of my investigator award. On the merozoite surface, RH5 forms part of a larger complex, interacting with CyRPA, RIPR and a fourth, GPI-anchored component. RH5, CyRPA and RIPR are each essential for erythrocyte invasion and are targets of antibodies that block invasion. Despite this, their functions are unknown, leaving a major gap in our understanding of erythrocyte invasion by Plasmodium falciparum. We will now undertake structure-function studies of the RH5:CyRPA:RIPR complex. Working with Simon Draper, we have developed eukaryotic expression systems to produce RH5, RIPR and CyRPA. We assembled them into a complex and showed that this is elongated, homogeneous and rigid by negative stain electron microscopy. Monoclonal antibodies targeting each component havebeen generated. We will now determine the structure of this recombinant RH5:CyRPA:RIPR complex using electron cryo-microscopy, and investigate where inhibitory monoclonal antibodies bind.
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Grant Details
Amount Awarded | 150000 |
Applicant Surname | Higgins |
Approval Committee | Science Enhancement Committee |
Award Date | 2016-12-05T00:00:00+00:00 |
Financial Year | 2016/17 |
Grant Programme: Title | Enhancement |
Internal ID | 101020/Z/13/A |
Lead Applicant | Prof Matthew Higgins |
Partnership Value | 150000 |
Planned Dates: End Date | 2020-10-01T00:00:00+00:00 |
Planned Dates: Start Date | 2017-01-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | South East |