Investigation on Structural Features and Antiaggregation Properties of Chaperonins and Chaperon Like Molecules

Molecular chaperones play essential and several roles in many cellular processes, including protein folding, targeting, transport, and are essential in fighting the consequences of protein misfolding and aggregation or enhancing disaggregation of toxic aggregates by clearance mechanisms. In particular, recent studies have attributed to some chaperones the capability to directly interact with amyloid aggregation-prone species of peptide involved in Alzheimer Disease in solution and/or suppress the associated toxicity. Among them are the principal heat-shock proteins (HSPs), the small HSPs, but also molecules the exhibit marked chaperon like activity, like milk caseins or BRICHOS domains. There are several mechanisms by which chaperones exert their protective action, many of which involve protein disordered regions. However, in many cases, the scarcity of structural data has impeded an understanding of the recognition and antiaggregation mechanisms, that result crucially important when considering how to screen for and characterize potential inhibitors of amyloidosis. Here we show how a human chaperonin, Hsp60, and intrinsically disorder colloids with marked chaperon-like activity, the milk caseins, can specifically influence Aβ40 fibrillogenesis. Inhibition studies are correlated with investigation on structural, self organization and stability properties of the chaperones under study performed by a battery of biophysical methods and aimed to understand what are molecular determinants responsible for their inhibitory action.