Project
Principles of specificity in cross-aggregation interactions
Protein aggregation is associated to a growing number of widespread debilitating disorders, such as Type-2 diabetes mellitus, Alzheimer’s and Parkinson’s disease. It involves the aberrant accumulation of misfolded proteins into ordered fibril structures, known as amyloids. This process is directed by interactions between short hydrophobic amino acid stretches with a strong tendency to self-associate, designated as aggregation prone regions (APRs). Aggregation-affiliated pathology is defined by cooperative deposition of a restricted number of heterologous proteins in distinct tissue or cell types. Mounting experimental evidence has extended this hetero-assembly selectivity down to the level of aggregation prone intermolecular interfaces, as the summated outcome of highly specific structurally and sequence dependent targeted interactions. This project will focus on exploring the mutational tolerance for heterologous interactions of structurally determined aggregation prone stretches, in an effort to uncover the fundamental principles that govern protein cross-talk engagement. The scope will be expanded to monitor the pivotal role of the cellular and molecular proteostasis network, as well as protein off-target effects in this process. Exploring the interplay between these potential modulators and the mutational landscape of aggregation prone regions will shed light into the unknown mechanisms that dictate both cooperative and targeted protein aggregation.