FEMSmicroBlog: About Malaria, crystals and alpacas

18-03-2022

Malaria remains a serious global health threat, killing over 1,300 children every single day. Its causative agent, Plasmodium falciparum, interacts with and enters into red blood cells with the help of surface proteins from the 6-cysteine protein family. The study “Structure of the Pf12 and Pf41 heterodimeric complex of Plasmodium falciparum 6-cysteine proteins” in FEMS Microbes investigated two of these surface proteins. Coralie Boulet explains for the #FEMSmicroBlog what the structure of 6-cysteine proteins can tell us about the parasite’s lifecycle. #FascinatingMicrobes

 

Malaria parasites and their surfaces

Despite important advances in recent decades towards malaria elimination, major challenges still stand in our way. These include the climate crisis, the low efficacy of the only malaria vaccine available, the lack of funding and the emergence of drug resistance.

Malaria is not caused by a virus or a bacterium, but by a single-cell parasite of the Plasmodium family. Its member Plasmodium falciparum causes the most severe disease after entering red blood cells. Within the cells, it can grow for two days while duplicating itself and creating up to 32 new parasites. These eventually exit the red blood cell while destroying it on their way out. The freshly released parasites can then enter other red blood cells and the cycle starts over again.

Proteins present at the surface of the parasite are particularly interesting as they interact with human cells and the immune system. For example, surface proteins from the 6-cysteine protein family are involved in different processes, like the entry into cells while others help the parasite hide from our immune system.

Plasmodium falciparum entering human red blood cells (arrows). Video replay is at twice the normal speed. Video file courtesy of Dr Greta E. Weiss.

 

Malaria surface proteins interact with each other

The study “Structure of the Pf12 and Pf41 heterodimeric complex of Plasmodium falciparum 6-cysteine proteins” published in FEMS Microbes looked at two members of the 6-cysteine protein family. Pf12 and Pf41 are highly abundant at the surface of the parasite during the entry phase so that malaria patients even develop antibodies against these two proteins. Interestingly, Pf12 and Pf41 bind to one another forming a complex, but until now it was not clear how exactly.

To solve the structure of these two proteins and their complex, the study used X-ray crystallography. After purifying and crystallizing the Pf12-Pf41 complex, the crystal was exposed to an X-ray beam and the diffraction pattern analyzed to resolve its three-dimensional structure.

This new structure of the Pf12-Pf41 complex is the first to provide insights at a high resolution on how 6-cysteine proteins interact with each other. Using such precise information allowed to identify the close contacts between Pf12 and Pf41 and how the two surface proteins embrace each other and no other malaria parasite protein.

Model of protein structures of Malaria surface proteins.
The structure of malaria surface proteins Pf12 and Pf41. From Dietrich et al. (2022).

 

Alpaca nanobodies breaking the bond

The study further harnessed the alpacas and their remarkable immune system to generate antibodies against Pf12 and Pf41. Interestingly, alpacas and other members of the camelid family produce small antibodies, termed nanobodies. These unconventional antibodies can be useful as they are less “bulky” and can therefore access smaller spaces.

Intriguingly, several nanobodies against the Pf12-Pf41 complex were able to block the formation of the complex. Again, using X-ray crystallography, the study showed how a nanobody bound to Pf12 thereby blocking off one critical binding site for Pf41.

Surprisingly, none of the generated nanobodies prevented the parasite from entering red blood cells in the culture dish. This might mean that Pf12 and Pf41 bind to other molecules during cell entry. Another option could be that their roles only become apparent in vivo, in the human body, as opposed to the culture dish. Lastly, they might have important functions during other stages of the parasite’s lifecycle. The true function of the Pf12-Pf41 complex remains mysterious for now as malaria parasites continue to intrigue scientists and threaten global health!

 

About the author of this blog

Coralie Boulet is a research officer at the Burnet Institute (Melbourne, Australia), in the group headed by Paul Gilson and Brendan Crabb. She investigates the Malaria parasite and explores new drug candidates to treat this devastating disease. She obtained her PhD from La Trobe University (Melbourne, Australia) in 2020, focusing on how the malaria parasite interacts with its host red blood cells. Passionate about the fascinating biology of this deadly parasite, she hopes to contribute to its eradication. When she is not busy culturing parasites in the lab, she is a committed climate activist.

About this blog section

The section #FascinatingMicrobes for the #FEMSmicroBlog explains the science behind a paper and highlights the significance and broader context of a recent finding. One of the main goals is to share the fascinating spectrum of microbes across all fields of microbiology.

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