Defining the functional role of a novel Plasmodium falciparum protein domain involved in liquid-liquid phase separation

Malaria constitutes an enormous global health burden, and there is an urgent need to identify new targets for antimalarial therapy to eradicate this parasitic disease. In the malaria parasite, P. falciparum, transcriptional regulation is fundamental to parasite development.

Apicomplexan Apetala 2 (ApiAP2) proteins are the main group of transcription factors regulating the malaria parasite lifecycle, acting as developmental switches between parasite life stages. Nine ApiAP2 proteins contain a highly conserved Apicomplexan-specific domain of unknown function, the ACDC domain.

We have found that this novel domain may act in oligomerization to drive the formation of cellular liquid condensates by Liquid-Liquid phase separation (LLPS).

I aim to characterize this domain by studying LLPS in vivo using a fluorescent reporter assay and directly in P. falciparum parasites. I will also determine in vitro protein interaction partners via protein pulldown assays and mass spectrometry.

Finally, I will create transgenic parasites to study the in vivo effect of modifications to this domain using CRISPR/Cas9. My training will be carried out during 30 months at Penn State in the lab of Prof. Manuel Llinás. I will then return to the lab of Mats Wahlgren at Karolinska Institutet for 6 months.

These studies will uncover the functional role for a unique, previously uncharacterized P. falciparum protein domain and will provide the first mechanistic explanation for LLPS in malaria parasites.