Tracking amyloid nucleation by deep mutational scanning
Speaker: : Benedetta Bolognesi, PhD - Junior Group Leader - Protein phase transitions in health and disease LAB - Institute for Bioengineering of Catalonia.
Organizer: IRB Barcelona
Date: Friday 16 April 2021, 12.00h
Title: "Tracking amyloid nucleation by deep mutational scanning"
Host: Xavier Salvatella, PhD - Group Leader - Laboratory of Molecular Biophysics, IRB Barcelona.
The formation of amyloid aggregates is the hallmark of many neurodegenerative conditions. Our lab uses deep mutational scanning (DMS) to quantify the effects of thousands of mutations on the nucleation of new aggregates formed by specific peptide and protein sequences. In this talk, I will explain how we mapped the effect of more than 14,000 mutations on the aggregation of the amyloid beta peptide (Aß), the main component of the plaques found in the brains of Alzheimer’s Disease (AD) patients. Unlike computational predictors and previous assays, the empirical nucleation scores obtained by DMS accurately identify all known mutations in Aß that cause familial AD, genetically validating that this cell-based assay is reporting on a mechanism likely to be very similar to the one causing human disease. The resulting Aß genetic landscape also reveals mechanistic insights into amyloid nucleation, including the role of charge and gatekeeper residues in the flexible peptide region - outside of the amyloid core - in preventing nucleation. To expand on the mechanistic implications of these results, I will also present unpublished data on new mutational libraries revealing how scrambling the Aß sequence, or truncating specific parts of it, can affect amyloid nucleation.