Protein aggregation acts as strong constraint during evolution

© 2012 Springer-Verlag Berlin Heidelberg. All rights are reserved. In the cell, it is the native protein conformation that exerts the biological function. Therefore, protein misfolding usually results in the impairment of essential cellular processes. In many cases, misfolded polypeptides self-assemble into cytotoxic aggregates, which formation impairs cell fitness. Accordingly, protein deposition is linked to the onset of an increasing number of deleterious human disorders such as Alzheimer's disease, Parkinson's disease, prion-associated transmissible spongiform encephalopathies, and type II diabetes. In these diseases, proteins usually self-assemble into highly ordered, β-sheet enriched structures known as amyloid fibrils. Importantly, the aggregation into amyloid conformations is not restricted to disease-related proteins but appears to be a generic property of polypeptides. This suggests that avoiding protein aggregation may act as important constrain in shaping proteins. In this chapter, we review experimental and theoretical studies supporting this view and discuss the different mechanisms evolved by nature to cope with the fitness cost imposed by protein aggregation.