Cracking the code of GTPBP3/MTO1: Structural and Functional characterization and links to rare human diseases

Mitochondria are central to ATP production, especially in energy-demanding heart and brain tissues. Defects in mitochondrial translation, often caused by missing post-transcriptional modifications of mitochondrial tRNAs, are a major cause of severe diseases. Among these, the C5-taurinomethylation of uridine 34 (τm5U34), catalyzed by the GTPBP3-MTO1complex, is essential for translation fidelity and respiratory chain function. Clinical mutations in genes encoding this complex cause the mitochondrial syndrome COXPD23 associated with cardiomyopathies or encephalopathies. The enzymatic reaction requires a complex set of cofactors and substrates including GTP, FAD, NADH, taurine and a folate derivative. Currently, the enzymatic mechanism, structural organization, and cellular consequences of the corresponding pathological mutations in GTPBP3 and MTO1 remain poorly understood.

In this proposed Ph.D. project, the candidate will pursue two main objectives: (1) reconstitute the tRNA modification pathway in vitro to define catalytic steps and assess the impact of clinical variants through biochemical techniques; (2) resolve the structural basis of enzyme cooperation using biophysical tools, X-ray crystallography, and cryo-EM. This project will deliver the first complete biochemical and structural mechanism of τm5U34 synthesis, explaining how its disruption is linked to pathologies, and open new avenues for therapeutic strategies against rare mitochondrial disorders.

The Ph.D. candidate will be supervised by Antoine Gedeon, Associate Professor of Biochemistry at Sorbonne Universitéand member of the RNAModBio research team of the Dev2A Laboratory at IBPS. Together, the team offers a highly collaborative and interdisciplinary research environment at the interface of structural biology, biochemistry, and RNA biology. The team is namely equipped with all tools for protein biochemistry and stopped-flow instruments for pre-steady state kinetics as well as a glovebox for anaerobic experiments. The candidate will also have access to state-of-the-art research facilities (Nanoimaging facility of Institut Pasteur and Synchrotron Soleil) and will benefit from close collaborations with leading experts, including Stéphanie Petrella (cryo-electron microscopy) and Frédéric Bonhomme (LC-MS) from Institut Pasteur/Université Paris Cité.

We are seeking a highly motivated candidate with a strong interest in structural biology, mechanistic enzymology, and RNA biology. Applicants should hold a Master's degree or equivalent in biochemistry, structural biology, or a related field. The successful candidate should demonstrate strong analytical skills, the ability to work both independently and as part of a multidisciplinary team, and excellent communication skills in English. Previous experience with manipulation under anaerobic conditions in a glovebox is a plus. Selection will be based on scientific excellence, motivation, and potential, without discrimination.