Dynamic hinge-motion of PfRIPR revealed by malaria invasion inhibitory antibodies

The PfPCRCR complex is essential for invasion of human erythrocytes by the deadliest malaria parasite, Plasmodium falciparum. Antibodies against each subunit of PfPCRCR prevent erythrocyte invasion and the PfRH5 component is currently the most advanced blood-stage malaria vaccine. Central within PfPCRCR is PfRIPR. This complex molecule contains a core and a flexible tail and allows PfPCRCR to bridge the parasite and erythrocyte during invasion. In this study, we generated a small panel of human monoclonal antibodies against PfRIPR. We structurally characterised four PfRIPR tail-binding antibodies in complex with PfRIPR fragments. We show that growth-inhibitory antibody RP.012 induces a kink in the PfRIPR tail while non-inhibitory antibodies do not. Furthermore, we show that these four antibodies modulate each other, either through antagonism or by acting synergistically. These studies have implications for the design of PfRIPR-based vaccine immunogens and indicate that the tail of PfRIPR undergoes essential conformational changes during erythrocyte invasion.