Structural and molecular analysis of the atypical E3 ubiquitin ligase MYCBP2 in Trypanosoma differentiation.
Supervisors:
Federico Rojas, Biomedical and Life Sciences, Lancaster University
Ben Collins, Queen's University Belfast
Helen Walden, School of Molecular Sciences, University of Glasgow
Summary:
Cell differentiation is tightly controlled by various molecular mechanisms, including the regulation of protein content. One key regulator of protein content is the ubiquitin-like molecule NEDD8. NEDD8 modifies target proteins altering their stability, localization, and activity. By modifying E3 ubiquitin ligases, NEDD8 influences the degradation of proteins involved in cell cycle progression and differentiation, ensuring that only the appropriate proteins are present as cells undergo differentiation. Through this regulatory mechanism, NEDD8 plays a crucial role in maintaining cellular identity and function during development.
Recently, we have identified an atypical E3 ubiquitin ligase in Trypanosoma brucei that appears to be regulated by neddylation during the parasite's differentiation. Our preliminary data shows removal of the NEDD8 moity of TbMYCBP2 when cells transition from the replicative to the cell cycle arrested form, suggesting this E3 ligase could have a regulatory function during differentiation. This research will shed light on TbMYCBP2’s role in T. brucei differentiation and uncover its unknown substrates, potentially revealing new therapeutic targets against T. brucei. The findings could significantly enhance our understanding of both trypanosome biology and the broader regulation of ubiquitin-like molecules across all nucleated organisms.
You will gain skills in cell culture, genetic manipulation (CRISPR), structural and biochemical studies, proteomics and data analysis.
In addition to developing a broad set of transferrable and commercial skills, you will gain expertise in both chemistry and biology, across two research labs. Within the Brown group at the University of Glasgow you will learn a variety of conventional and novel techniques and methodologies relating to biofilm culture in vitro. Within the Scott group at the University of Strathclyde you will develop skills in synthetic organic chemistry and drug design, and use state-of-the-art techniques, such as Biomolecular NMR, Native Ion Mass Spectrometry and target engagement assays.