Defining the role of protein glutathionylation in proteostasis and cellular stress adaptation

About the project

About the Project Protein glutathionylation is a reversible post-translational modification in which glutathione is added to protein cysteine residues. It has traditionally been viewed as a protective response to oxidative stress. Our recent work, however, suggests that glutathionylation has a much broader role in controlling protein interactions, active-site accessibility and the organisation of the proteome. A major challenge has been that conventional proteomic workflows can disrupt or remove cysteine-linked glutathione during sample preparation. We have recently developed an enrichment-free mass spectrometry strategy that preserves endogenous glutathionylation and enables site-resolved mapping across biological systems. Our preliminary data indicate that glutathionylation is widespread, dynamic and enriched at protein-protein interfaces and active sites. This studentship will build on these findings to determine how glutathionylation regulates proteostasis and cellular adaptation to stress. The successful candidate will join a highly collaborative project spanning the laboratories of Professor Kostas Thalassinos and Dr John Labbadia at UCL, together with Waters Corporation. The project combines advanced mass spectrometry with molecular and organismal biology and is ideally suited to a student who wants to work across disciplinary boundaries. The student will develop quantitative mass spectrometry workflows for glutathionylation using advanced instrumentation, including the Waters Xevo MRT. They will combine quantitative proteomics and crosslinking mass spectrometry to determine how glutathionylation remodels protein interaction networks and protein-folding machinery. Functional studies in mammalian cells and Caenorhabditis elegans will establish how these molecular changes influence proteostasis, stress resistance and tissue health. The project will also investigate the glutaredoxins and glutathione transferases that control glutathionylation dynamics and will integrate proteomic and metabolomic measurements to define links between glutathionylation and cellular metabolism. The project offers unusually broad training. At UCL, the student will receive hands-on training in quantitative proteomics, crosslinking mass spectrometry, advanced data analysis, mammalian cell culture, C. elegans genetics , RNAi, stress biology and functional proteostasis assays. The student will have direct access to the UCL Mass Spectrometry Science Technology Platform (MS-STP), a multi-million-pound research infrastructure housing state-of-the-art instrumentation for proteomics and structural mass spectrometry. The student will also undertake a minimum three-month industrial placement with Waters Corporation in Wilmslow, primarily during Years 2 and 3. They will work alongside Waters scientists and receive specialist training in metabolomics, advanced acquisition strategies, instrument evaluation and analytical method development. This provides experience of industrial research and development that cannot be replicated in an academic environment alone. We are looking for a motivated and intellectually curious candidate with a strong background in biochemistry, molecular biology, chemistry, biotechnology or a related discipline. Previous mass spectrometry experience is not essential. More important are enthusiasm for mechanistic biology, quantitative experimentation and learning new technologies. The project would particularly suit a person who enjoys integrating biological experiments with analytical and computational approaches and who wants to develop skills relevant to both academic and industrial careers.

Research areas