Understanding and predicting protein misfolding and aggregation: Insights from proteomics

Protein misfolding and aggregation are being found to be associated with an increasing number of human diseases and premature aging, either because they promote a loss of protein function or, more frequently, because the aggregated species gain a toxic activity. Despite potentially harmful, aggregation seems to be a generic property of polypeptide chains and aggregation-prone protein sequences seem to be ubiquitous, which, counterintuitively, suggests that they serve evolutionary conserved functions. The in vitro study of individual aggregation reactions of a large number of proteins has provided important insights on the structural and sequential determinants of this process. However, it is clear that understanding the role played by protein aggregation and its regulation in health and disease at the cellular, developmental, and evolutionary levels require more global approaches. The use of model organisms and their proteomic analysis hold the power to provide answers to such issues. In the present review, we address how, initially, computational large-scale analysis and, more recently, experimental proteomics are helping us to rationalize how, why and when proteins aggregate, as well as to decipher the strategies organisms have developed to control proteins aggregation propensities.