A Simple Principle for Understanding the Combined Cellular Protein Folding and Aggregation

Abstract

Proteins can undergo kinetic/thermodynamic partitioning between folding and aggregation. Proper protein folding and thermodynamic stability are crucial for aggregation inhibition. Thus, proteinfolding principles have been widely believed to consistently underlie aggregation as a consequence of conformational change. However, this prevailing view appears to be challenged by the ubiquitous phenomena that the intrinsic and extrinsic factors including cellular macromolecules can prevent aggregation, independently of (even with sacrificing) protein folding rate and stability. This conundrum can be definitely resolved by 'a simple principle' based on a rigorous distinction between protein folding and aggregation: aggregation can be controlled by affecting the intermolecular interactions for aggregation, independently of the intramolecular interactions for protein folding. Aggregation is beyond protein folding. A unifying model that can conceptually reconcile and underlie the seemingly contradictory observations is described here. This simple principle highlights, in particular, the importance of intermolecular repulsive forces against aggregation, the magnitude of which can be correlated with the size and surface properties of molecules. The intermolecular repulsive forces generated by the common intrinsic properties of cellular macromolecules including chaperones, such as their large excluded volume and surface charges, can play a key role in preventing the aggregation of their physically connected polypeptides, thus underlying the generic intrinsic chaperone activity of soluble cellular macromolecules. Such intermolecular repulsive forces of bulky cellular macromolecules, distinct from protein conformational change and attractive interactions, could be the puzzle pieces for properly understanding the combined cellular protein folding and aggregation including how proteins can overcome their metastability to amyloid fibrils in vivo.

Keywords: Protein folding; aggregation; chaperones; charges; excluded volume; intermolecular repulsive forces; macromolecules; metastability..