RNA processing in the malaria parasite

Malaria kills about 400,000 children each year in sub-Saharan Africa. It is caused by the single-celled eukaryote Plasmodium, a member of the apicomplexa group of parasites which also include Toxoplasma. These parasites have an extraordinary evolutionary history, for they were once photosynthetic, and contain a remnant chloroplast, known as an apicoplast. Many commonly-used anti-malarial drugs work by inhibiting RNA transcription and protein synthesis in the apicoplast. However, there is rising drug resistance so new drugs are urgently required. Previous research have shown that long, polycistronic RNA transcripts are synthesized in the apicoplast. These primary transcripts and are rapidly cleaved to mature RNA molecules. A key proteins involved in this process has been identified, an RNA binding protein (PPR1), a member of the pentapeptide repeat protein family. It has been shown that the protein is essential, and have established a conditional knock-down cell line. In addition, we have established a heterologous expression system for it, and have shown that PPR1 is functional in vitro.
A number of essential proteins that control apicoplast RNA processing have also been identified , including PPR1 (Hicks, eLife, 2019) and an RNAase. We now wish to see how these proteins work together to control RNA processing.
Depending on the interests of the PhD student, the options are:
– To examine how a PPR1 knock-down affects cellular morphology and life-stage progression (This is in conjunction with collaborator Prof Ross Waller, University of Cambridge)
– To obtain a structure of PPR1
– To characterize the newly-identified RNAse, and to determine if it interacts with the PPR1 protein.
– To identify further RNA-binding proteins in the apicoplast using the OOPs protocol (Queiroz et al, 2019: https://www.nature.com/articles/s41587-018-0001-2). Newly identified proteins can then be purified, and the genes encoding them knocked out.
For info, see Hicks et al 2019 ‘An essential pentatricopeptide repeat protein in the apicomplexan remnant chloroplast’: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899631/ Nisbet and Hicks 2016 ‘Transcription of the apicoplast genome’

UKRI project details

Basic Science

Sep 2023 — Sep 2027

United Kingdom