Reference : PhD Gulnara Yusupova
It is known that alterations in diverse range of translational machinery cause an extensive and growing catalogue of human diseases. Molecular mechanisms responsible for differences in longevity between living organisms are largely unknown, but it was shown that it is related to the fidelity/accuracy of protein translation on the ribosome. Thus, the study of ribosome is important not only for the fundamental knowledge, but also for developing new therapeutic, which will target the ribosome.
The major goal of PhD project is to understand the molecular mechanisms of the fidelity of eukaryotic ribosome to the genetic code on atomic level. The mechanisms cannot be understood unless the structures of the participating macromolecules are known at atomic resolution. Recently our group succeeded in solving the first structure of the full eukaryotic 80S ribosome from yeast(Mw 3 400 000 Da), the biggest asymmetric macromolecule solved by x-ray analysis. Presently, we are the only group in the world working on the structure of full 80S eukaryotic ribosome using X-ray analysis.
The process of translation carried by the ribosome consists of several sequential steps and involves diverse factors that facilitate and regulate the process. Deregulation of translational factors leads to disruption of cellular processes and can result in cell death. In eukaryotes, elongation factor 2 (eEF2) plays the central role in the protein synthesis catalyzing movement of the 80S ribosome on a messenger RNA (mRNA). Normally eEF2 insures that the ribosome reads triplets of mRNA in a correct frame to synthesize proper proteins. However, being the main contributor to the process of elongation, eEF2 is involved in non-canonical translating mRNA when a slippage or shift occurs in a reading frame. Compelling experimental data indicate that non-programmed frameshifting triggers rare disorders, which can be exemplified by a progressive Huntington disease marked by neuron degeneration. The project, in which perspective PhD student will be involved, aims to solve the crystal structures of the yeast 80S ribosome in the complex with eEF2 in the state modeling a frameshift event. By other words, the goal is to specify atomic details of the mRNA movement and slippage on the ribosome and, as such, will suggest potential targets for treatment of disorders triggered by ribosomal frameshifting.
To reach this goal PhD student will use a wide range of approaches, including X-ray crystallography, cryo-electron microscopy, biochemistry methods, molecular genetics.
Date limite de candidature : 1 novembre 2018