Mapping the impact of post-translational modifications on protein aggregation.

A diverse group of principal widespread diseases, including Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), type II diabetes mellitus and many others, shares a single common feature referring to the constant build-up of protein deposits, which causes various symptoms of growing severity (inflammation, tissue degeneration and full organ disfunction). Aberrant aggregation is promoted by short hydrophobic segments, located within protein sequences, that tend to clump together forming insoluble protein stacks. This process occurs primarily as an outcome of protein overexpression or instability, due to pH or temperature variations, mutations or post-translational modifications. Modified protein building blocks are gradually linked to several protein aggregation disorders. However, this is mostly reported on a case by case basis, and as a result, we still lack a thorough understanding of their direct influence and importance on the molecular mechanisms behind major protein aggregation events. In this project, we propose to investigate the general rules dictating the relation of post-translational modifications to aggregation propensity by providing a comprehensive analysis of their linear impact on featuring self-associating regions of proteins that act as major determinants of aggregation.