Structure and function of a parasite RNA processing complex
Supervisors:
Prof Lilach Sheiner, School of Infection & Immunity
Prof Paula da Fonseca, School of Molecular Biosciences
Dr Shikha Shikha, School of Infection & Immunity
Summary:
Despite their critical and near ubiquitous role in cell biology, our textbook understanding of mitochondria is almost solely based on commonly studied model organisms and we suffer a huge gap of knowledge of divergent mitochondrial biology.
The mitochondrion of apicomplexan parasite provide an excellent example, where mitochondrial biology repeatedly surprises the field and re-defines our global understanding of mitochondrial biology.
For example, while almost all ribosomes are made up of 2 long rRNA molecules, we recently discovered that the mitochondrial ribosome Toxoplasma gondii is made up of tens of very short rRNA molecules (Shikha et al; under revisions). This extreme and surprising finding raise numerous questions about how the parasite mitochondrial rRNA is transcribed and processed before to generate the essential mitoribosome.
In this project we will use proteomics, genetic manipulation (CRISPR/Cas9 assisted) and structure biology (via single particle by cryoEM) to reveal and define the key players in mitochondrial rRNA biogenesis in these divergent and medically important parasites.
Mitochondrial pathways of Toxoplasma and of its close relative, malaria causing, Plasmodium spp, are demonstrated to be selectively sensitive to inhibitor, which is gradually presenting a growing number of new drug targets. The divergent and essential nature of the mitochondrial rRNAs in these parasites likely rely on parasite specific and essential enzymes, and thus might present new targets for drug discovery in the future.