Understanding the architecture of the Plasmodium-interspersed repeat proteins

Employing structural biology to understand the evolution of malaria surface protein families.

Only a few proteins are sent to the surfaces of red blood cells infected with malaria parasites. Their exposure is risky, as it alerts the immune system of the infected individual to their presence. For this reason, these proteins have expanded into large and diverse protein families, which can be deployed one-by-one, helping the parasite to stay safe.

One of the largest and most ubiquitous of these protein families is the Plasmodium-interspersed repeat proteins, or PIRs. These proteins can be found in the thousands in some parasite genomes. But which of the different groups of small variant surface antigens generated by different Plasmodium species are PIRs?

To answer this question, Tom Harrison, armed with the idea that structure remains more conserved than sequence, decided to solve a PIR protein structure. This revealed the PIR proteins to have a novel architecture. Importantly this differed from the architecture of the RIFINs, the major small variant surface antigen of the deadly human malaria parasite, Plasmodium falciparum. 

Structure-based sequence analysis then allowed Tom to explore which of the Plasmodium parasites have PIR proteins. Those that do, include human infective Plasmodium vivax and Plasmodium ovale, as well as rodent-infective parasites, suggesting that the PIRs appeared after the divergence of these species.

While this study reveals much about the membership of the PIR protein family and its evolution, mysteries still exist about their function. What do these enigmatic proteins do and why has the parasite evolved to expose them on its surface? Do they modulate human immune cell function, as the RIFINs? Only further experiments will tell. 

Harrison, T.E., Reid, A.J., Cunningham, D., Langhorne, D. and Higgins, M.K. (2020) Structure of the Plasmodium-interspersed repeat proteins of the malaria parasite. Proc. Natl. Acad. Sci. USA 117 32098-32104