Protein misfolding and aggregation: new examples in medicine and biology of the dark side of the protein world

Abstract

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.

Cutting Edge Structural Protein from the Jaws of Nereis virens

“…Historically, the tendency toward fibrillization was thought to be an exceptional property of proteins, such as R-synuclein, -amyloid, PrP, and so on, typically associated with the various neurodegenerative amyloidoses (reviewed in ref 38). Recent focus has shifted, however, to diverse proteins for which fiber formation appears to be completely unlinked to disease (reviewed in ref 39). Furthermore, it has been hypothesized that amyloidogenicity may be an inherent property of all polypeptides given appropriate conditions.…”

Application and use of differential scanning calorimetry in studies of thermal fluctuation associated with amyloid fibril formation

“…Amyloid fibrils are highly ordered protein aggregates associated with several neurodegenerative and non-neuropathic diseases (Sipe and Cohen 2000;Caughey and Lansbury 2003;Selkoe 2003;Stefani 2004;Chiti and Dobson 2006;Eisenberg and Jucker 2012). The precursor proteins and peptides implicated in these diseases, regardless of the large variation in the amino acid sequences or the native structures, aggregate into amyloid fibrils that contain extensive β-sheet structures, where the β-strands are oriented perpendicular to the axis of the fibrils (Sunde and Blake 1997;Jahn et al 2010;Tycko 2011).…”

Are Proposed Early Genetic Codes Capable of Encoding Viable Proteins?

“…However, if proteins need to be optimized during evolution to avoid aggregation, the question arises whether newly born ('de novo') proteins are viable and whether they pose a potential risk to the organism (Wu 2013). Considering the early stages of protein evolution, the problem might have been more serious for ancient proteins that existed in an environment devoid of today's elaborate cellular mechanisms acting to reduce the risk of aggregation (Monsellier 2007;, Reumers 2009aStefani 2004). Based in this information, we expect that earlier codes are biased towards avoiding to produce proteomes with high aggregation propensities.…”