Periodic Reporting for period 2 - RIBOFOLD (Ribosome Processivity and Co-translational Protein Folding)
Reporting period: 2020-02-01 to 2021-07-31
Defects in protein folding disturbs the cellular proteostasis, which can result in debilitating diseases. Single amino-acid substitutions can disrupt a protein’s structure in the cell to cause, for instance, cystic fibrosis, sickle cell anemia, cataract, Huntington’s disease, or retinitis pigmentosa. The molecular pathology of these diseases is a perturbation of the native three-dimensional structure leading to a misfolded protein that can no longer execute its function and is prone to aggregation and rapid degradation. Furthermore, mutations in natively disordered proteins, such as α-synuclein, tau protein or amyloid β-peptide, can cause aggregopathies, such as Parkinson’s and Alzheimer’s.
Despite its importance for understanding human diseases, the mechanisms of co-translational folding and the link between the speed of translation and the quality of protein folding are poorly understood. The aim of the RIBOFOLD project is to understand when, where and how proteins emerging from the ribosome start to fold, how the ribosome and auxiliary proteins bound at the polypeptide exit affect nascent peptide folding, what causes ribosome pausing during translation, and how pausing affects nascent peptide folding. To address these questions, we utilize a toolbox of ensemble and single molecule biophysical techniques to monitor translation and protein folding simultaneously at high temporal resolution. We expect that these results will open new horizons in understanding co-translational folding and help understand the molecular basis of many diseases.
The results obtained so far are described in three papers and two manuscripts that are in revision or submitted for publication and presented on 11 international scientific conferences. While the usual number of participant to such conferences varies between 50 and 300, we were able to present two oral talks at the Biophysical Society Meeting 2020 and European Biophysical Society in 2021, which attracts about 5000 and 1000 participants, respectively. The results were also disseminated through a Youtube webinar (https://www.youtube.com/watch?v=EHWcOoNwzQQ) which collected >600 views so far. We developed a web site and a Twitter showroom to present our research to broader audiences, including not only scientists of different disciplines, but also lay public interested in science.