From sequence to structure determinants of functional and non-functional protein aggregation /

Resumen

The study of protein aggregation represents a challenging research field which embraces from biomedical to biotechnological areas. The growing number of human diseases associated to the deposition of amyloid aggregates as well as the formation of intracellular protein deposits during the recombinant production of therapeutic proteins in cell factories has pushed the research to understand and develop strategies against protein aggregation. Until the past decade, amyloid aggregation was thought to be only associated with pathological amyloid states or unsuccessful folding during heterologous protein production. This idea was radically changed with the discovery of amyloid fibers being used for functional purposes in bacteria, fungi, insects, invertebrates and humans. This suggests that the amyloid propensity is not confined to toxic amyloidosis but it m ay be considered as an intrinsic property of the polypeptide chain that allows the build up of macromolecular assemblies with exceptional structural properties. In the present thesis we have used a set of biophysical and computational tools combined with in vitro and in vivo models to characterize both functional and non-functional aggregation. On one side, we have analyzed the specific role of bacterial peptides in biofilm amyloid formation and virulence in S. aureus. On other side, structurally distinct protein models have been used to study the role of molecular determinants such as disulfide bond crosslinking, harsh environmental conditions and intrinsic amyloidogenic propensities in the formation of non-functional aggregates. Overall, the data reported here underline the tight control exerted by Nature to allow functional amyloid assembly while counterbalancing intrinsic and extrinsic factors that might lead to toxic amyloid aggregation.