Oligomerization preceding amyloid fibril formation: a process in common to intrinsically disordered and globular proteins

Abstract

Neurodegenerative diseases present a big burden to society. At the molecular level many of them – if not all – show protein aggregation (as an epiphenomenon or as a cause). The knowledge on details of thermodynamics and kinetics as well as structure of the protein aggregates, especially the early and soluble oligomers, may help in designing inhibitors for early stages of such diseases. Here, a possible outlook on more general mechanism for their formation is discussed. The oligomers of amyloid forming proteins, which are present prior and during nucleation and amyloid fibril formation, are claimed to be toxic to cells. Oligomers of the globular proteins and the intrinsically disordered proteins (IDPs), form in vitro upon partial denaturation and renaturation, respectively. Often they form if the sample is heated or freeze-thawed for a few cycles. A question is asked if this does not highlight one important property in common to globular proteins and IDPs, namely, a high energetic barrier dividing such oligomers from the monomers. This also would imply existence of two populations of states, one, the monomer – being metastable – at least under the conditions, which promote fibril formation.

• protein aggregation
• oligomers
• amyloid fibrils
• intrinsically disordered proteins