B05: Predicting the impact of biosynthetic fidelity on protein folding

The declining fidelity of mRNA production and translation contributes to protein misfolding and aggregation. Transcription is a highly controlled process involving e.g. proofreading to reduce sequence errors. Yet chronic cellular stress (e.g. during aging or oxidative stress), DNA damage and imperfect mRNA processing reduce the fidelity of mRNA synthesis and increase the number of mRNA sequence errors. Such mRNA sequence errors may impact on cell physiology via changing mRNA stability and localization, and/or by changing protein stability, localization and structure. Here, we will explore consequences of mRNA sequence alterations on protein structures, which may eventually lead to pathological phenotypes. In addition, cellular stress and changes in energy metabolism affect the fidelity of translation, which may further contribute to protein misfolding. To systematically address how the fidelity of mRNA and protein synthesis contribute to protein (mis)folding, we will combine recent advances in proteome-scale protein structure analysis with computational modelling. This approach will enhance the mechanistic interpretation of the data and identify proteins and protein regions that are prone to change their folding upon mRNA sequence variation or altered translation fidelity. We will establish approaches that allow for distinguishing misfolding that directly results from reduced fidelity of mRNA and protein biosynthesis, from adaptive folding changes in response to cellular stress. Thereby we aim to explain why certain proteins are particularly vulnerable to fidelity decline (e.g. caused by transcriptional- or oxidative stress).