Pros And Cons Of Protein Aggregation

Protein aggregation: Toxicity and function, two sides of the same coin

Protein misfolding and aggregation is linked to the onset of more than 40 human diseases. Although protein aggregation is potentially harmful for the cell and usually compromises its fitness, the vast majority of proteins contain sequences that predispose them to aggregate. The reason behind this apparent contradiction is that the presence of these sequence stretches provides a number of structural and functional advantages, as long as they are kept under control.

A growing interest in the study of protein aggregation

The study of protein aggregation has remained for long time as a marginal research topic restricted to the biotechnological area. Protein aggregates were

As a general trend, to function, the polypeptide chains that come out from ribosome in an unfolded conformation should adopt a defined three-dimensional structure known as the native state. In many cases, when this active conformation cannot be attained or maintained, misfolded proteins tend to self-assemble either intra or extracellularly to build up insoluble deposits. The formation of these aggregates promotes the loss of the embedded proteins function, saturates the protein quality control machinery constituted by proteases and chaperones, promotes aberrant interactions and the co-aggregation of essential cellular proteins and can be toxic per se. Thus it is not surprising that protein aggregation becomes associated to pathological states. The proteins involved in these disorders do not share any sequential or structural similitude. They can be intrinsically disordered like -synuclein in Parkinson, predominantly constituted by -sheets such as SOD1 in ALS or alternatively -helical like insulin in injection-localized amyloidosis. They can be small and monomeric like amylin in type II diabetes or big and multimeric like transthyretin in familial polyneurophaty. Protein aggregation contradicts the one sequence / one structure / one function biology dogma, because independently of their sequence and native conformation, when these proteins aggregate into their toxic species they converge to form macromolecular assemblies sharing a common fibrillar architecture, known as amyloid fibrils. These conformations are characterized by a polypeptide backbone organization in a cross- disposition, which consists of a succession of contiguous -strands stacked perpendicularly to the fibril axis. For many years, the characterization of the cross--sheet motif with high resolution structural techniques like NMR and X-ray diffraction remained elusive. Therefore, the