Visualising a bridge between a malaria parasite and a human erythrocyte that occurs during erythrocyte invasion

For the most-deadly malaria parasite, Plasmodium falciparum, to replicate within our bodies, it must get inside our red blood cells. At the heart of this invasion process is a large assembly of parasite proteins containing five components, PfRH5, PfCyRPA, PfRIPR, PfCSS and PfPTRAMP. Each of these is essential for successful erythrocyte invasion and antibodies against these components can block erythrocyte invasion and protect from the symptoms of malaria. However, we know remarkably little about how this protein complex functions.

To answer these questions, Brendan Farrell set out to determine the structure of the PfRCR complex which contains PfRH5, PfCyRPA and PfRIPR. While we already knew what PfRH5 and PfCyRPA look like, we didn’t know the structure of PfRCR or its PfRIPR component. By using cryo-electron microscopy, Brendan was able to see PfRCR for the first time. In particular, this showed PfRIPR it to consist of an ordered core which binds to PfCyRPA, flexibly attached to an elongated tail.

We also tested the function of PfRH5. A previous study had suggested the PfRH5 might disassemble and insert into the erythrocyte membrane during the invasion process. Nawsad Alam therefore therefore locked the two halves of PfRH5 together using disulphide bonds and Melissa Hart and Ellen Knuepfer showed that this did not affect the ability of PfRH5 to mediate erythrocyte invasion. Therefore, PfRH5 does not come apart to insert into the membrane during invasion.

Instead, Brendan, found that the PfRIPR tail binds to the PfCSS:PfPTRAMP proteins which are found on the parasite membrane. The PfRIPR core assembles with PfCyRPA and PfRH5 to form a unit which binds to the human receptor basigin on the erythrocyte. Therefore, PfRIPR forms a bridge, joining the parasite membrane to the erythrocyte membrane.

This new view of PfRIPR will help us to design and test improved components for a more focused blood stage malaria vaccine. It also provides a better view of what this set of parasite proteins are doing during invasion, opening the way to further experiments to understand how this elusive parasite finds itself a safe home in which to replicate.

Farrell, B., Alam, N., Hart, M.N., Jamwal, A., Ragotte, R.J., Walters-Morgan, H., Draper, S.J., Knuepfer, E. and Higgins, M.K. (2023) Structure of the PfRCR complex which bridges the malaria parasite and erythrocyte during invasion. Nature 625 578-84