Mechanisms and consequences of protein aggregation: the role of folding intermediates

Protein aggregation, being one of the hottest topics of modern protein science, is recognized now as a serious biomedical and biotechnological problem. Protein aggregation is considered as a causative factor (or at least an associated symptom) of a wide spectrum of human pathologies. Furthermore, aggregation and precipitation are known to trammel recombinant protein production, as well as to affect the manufacture, storage and delivery of proteinaceous drugs. Therefore, this topic attracts the serious attention of many researchers, a conclusion that follows from the average daily publication of 7-8 scientific papers dedicated to the various aspects of protein aggregation. However, the situation was rather different 15-20 years ago when it was believed that the formation of protein aggregates causing the irreversibility of unfolding or denaturation of some proteins was nothing more than an annoying experimental artifact, hampering the detailed characterization of the unfolding/denaturation processes. At that time, only a few laboratories (including the laboratory of Prof. Anthony L. Fink) seriously worked on understanding the molecular mechanisms of this "artifact". In this review, we summarize some of the early work of Tony Fink on aggregation, of protein folding intermediates and on the analysis of the structural consequences of this process.