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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.

£150,000

05 Dec 2016

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
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
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