Protein aggregation processes: In search of the mechanism

Abstract

Amyloid formation typically follows a time course in which there is a long lag period followed by a rapid formation of fibrils. In this review, I show that the standard mechanisms of polymerization need to be expanded to consider that the monomeric proteins/peptides involved in amyloid formation are intrinsically disordered and exist as an ensemble of disordered-collapsed states. The review focuses primarily on events which occur in the long lag period defining these as protein folding issues, coupled with formation of oligomers. Experimental methods to explore folding and oligomerization issues over a wide range of protein concentrations using primarily fluorescence and 19F-NMR methods are discussed.

Scheme 1.

Figure 1.

A representation of the possible states of a monomer of intrinsically disordered proteins. It should be recognized that both the disordered–denatured and the disordered–collapsed states represent ensembles of different conformational forms.

Figure 2.

A simplified representation of different dimeric forms. As discussed in the text, the formation of a dimer would be a second-order process with the rate depending on the concentration of a monomeric species. The conversion from a disordered–collapsed state to a structured state is a first-order process independent of concentration.

Scheme 2.