The Yin and Yang of protein folding

Abstract

The study of protein aggregation saw a renaissance in the last decade, when it was discovered that aggregation is the cause of several human diseases, making this field of research one of the most exciting frontiers in science today. Building on knowledge about protein folding energy landscapes, determined using an array of biophysical methods, theory and simulation, new light is now being shed on some of the key questions in protein-misfolding diseases. This review will focus on the mechanisms of protein folding and amyloid fibril formation, concentrating on the role of partially folded states in these processes, the complexity of the free energy landscape, and the potentials for the development of future therapeutic strategies based on a full biophysical description of the combined folding and aggregation free-energy surface.

Fig. 1. A schematic energy landscape for protein folding and aggregation.

The surface shows the multitude of conformations ‘funneling’ towards the native state via intramolecular contact formation, or towards the formation of amyloid fibrils via intermolecular contacts. Recent experiments have allowed the placement of different ‘intermediate’ structures on both pathways [2,50], although detailed structural models for many of these species are not yet available. Furthermore, the species involved in converting kinetically stabilized globular structures into the thermodynamic global free energy minimum in the form of amyloid fibrils for different proteins is currently not defined.

Fig. 2. A schematic representation of the factors influencing protein folding and aggregation events in vivo.

Molecular chaperones (Hsp) as well as the ubiquitin-proteasome pathway (Ub) prevent protein unfolding and aggregation by facilitating refolding or degradation, respectively. An increased population of misfolded proteins as a result of genetic or extracellular factors may lead to a saturation of these defense mechanisms and subsequently to an increase in protein aggregation. Partially folded proteins associate with each other to form small, soluble oligomers that may undergo further assembly into protofibrils, oligomeric pores or mature fibril deposits (scale bars represent 100 nm or 10 nm for the amyloid pore) [37,38]. Whether these species can interconvert, or whether the indicated structures represent assembly end products, is dependent on the assembly conditions and the identity of the polypeptide sequence [38,50]. The toxicity of different species and their role in the development of disease is currently being explored for different protein systems [39].