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Unravelling the Nascent Code: Signals sensed and transmitted by the nascent chain to acquire its functional state or reprogram gene expression

Final Report Summary - THE NASCENT CODE (Unravelling the Nascent Code: Signals sensed and transmitted by the nascent chain to acquire its functional state or reprogram gene expression)

Emerging biochemical and biophysical data strongly suggest that the transformation of the potential set of proteins, encrypted in the genome of the cell, into its actual vital functional set, is a function not just of the genetic code but of an additional layer of information encoded within the newly synthesised polypeptide nascent chain (NC). Depending on the cellular status and starting on the very first steps of synthesis, a variety of signals are indeed formed within the ribosome and the evolving NC. These signals, by acting directly on the ribosome or by recruiting additional cellular machines, have the ability to pause or even abrogate the synthesis itself of the NC or to guide it towards the acquisition of its final functional state and cellular location. As a result, the translational step, becomes a new strategic pivotal point to sense the specific cellular status and accordingly complete, abrogate or re-program gene expression. Due to its distinct nature, I prefer to refer to this ensemble of signals as “the nascent code”. Despite our knowledge on the importance and existence of the nascent code, we know very little about its mechanism of action. The ultimate goal of this research line is to unravel the molecular determinants of the nascent code elucidating at the structural level its role during gene expression and regulation. Capitalising on the gathered expertise within our group and our collaboration partners, as well as the ideal environment offered by our Host Institute, CIC bioGUNE, we have settled on using a multidisciplinary approach based on x-ray crystallography, NMR and CryoEM to investigate from a macroscopic to atomic level the dynamics, structure and interactions of some the key players involved in the vital process of protein synthesis. The results obtained on the mechanism of action of chaperones and small molecules, among which new anti-infective agents, pave the way for the development of a new set of tools to control and modulate the essential ability of the cell to regulate gene expression at the translational level.