Protein misfolding and aggregation: new examples in medicine and biology of the dark side of the protein world.
The data reported in the past 5 years have highlighted new aspects of protein misfolding and aggregation. Firstly, it appears that protein aggregation may be a generic property of polypeptide chains possibly linked to their common peptide backbone that does not depend on specific amino acid sequences. In addition, it has been shown that even the toxic effects of protein aggregates, mainly in their pre-fibrillar organization, result from common structural features rather than from specific sequences of side chains. These data lead to hypothesize that every polypeptide chain, in itself, possesses a previously unsuspected hidden dark side leading it to transform into a generic toxin to cells in the presence of suitable destabilizing conditions. This new view of protein biology underscores the key importance, in protein evolution, of the negative selection against molecules with significant tendency to aggregate as well as, in biological evolution, of the development of the complex molecular machineries aimed at hindering the appearance of misfolded proteins and their toxic early aggregates. These data also suggest that, in addition to the well-known amyloidoses, a number of degenerative diseases whose molecular basis are presently unknown might be determined by the intra- or extracellular deposition of aggregates of presently unsuspected proteins. From these considerations one could also envisage the possibility that protein aggregation may be exploited by nature to perform specific physiological functions in differing biological contexts. The present review focuses the most recent reports supporting these ideas and discusses their clinical and biological significance.
Stefani
Massimo
M
Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy. stefani@scibio.unifi.it
D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D004194:Disease; D019143:Evolution, Molecular; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000494:pharmacology / Q000502:physiology*
D000682:Amyloid; D011506:Proteins