Amyloid fibrils: Dark side of protein aggregation

A wide range of peptides and proteins has the unique propensity to self-assemble into insoluble fibrillar quaternary structure enriched in intermolecularly hydrogen bonded β-sheets [1,2]. The accumulation of these highly ordered aggregates in human tissues is associated with a number of devastating disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases, type II diabetes, atrial amyloidosis, etc. [3–5]. It is now generally accepted that molecular basis of amyloid formation lies in the incorrect protein folding, or misfolding [6,7]. This is readily achievable because the compactness of native state is compromised by the loss of configurational entropy during polypeptide folding and repulsive electrostatic interactions. Due to small difference between stabilizing and destabilizing forces, native protein structure is only marginally stable, so that any variation in physicochemical properties of polypeptide surroundings may trigger the protein leaving of the native folding pathway and entering the off-folding route, one of which is formation of the stable fibrillary aggregates from the unstable partially unfolded intermediates.