Influence of the polypeptide environment next to amyloidogenic peptides on fibril formation

Alternative folding or fibril formation of proteins is associated with many diseases. Although uncertainty remains for many diseases as to whether the fibrils themselves constitute the main pathogenicity factor, the biophysics or molecular steps leading to fibrils cannot easily be reduced to a common denominator. To date, it is known that fibrils can form (i) upon aberrant (over-)production or false processing, (ii) upon infection with prions that act as seeds and induce unfolding of a thus far native protein--as has been shockingly experienced during the bovine spongiform encephalopathy episode, (iii) when mutations are present that increase the propensity of an otherwise stable protein to aggregate, or (iv) when mutation decreases the overall stability of an individual protein. This review intends to highlight some of the biochemical and biophysical mechanisms that favor fibril formation. Special emphasis is given on the relevance of the polypeptide environment of amyloidogenic segments and the currently discussed driving forces of fibril formation.