Protein aggregation in health and disease: A looking glass of two faces.

Protein molecules organize into an intricate alphabet of twenty amino acids and five architecture levels. The jargon "one structure, one functionality" has been challenged, considering the amount of intrinsically disordered proteins in the human genome and the requirements of hierarchical hetero- and homo-protein complexes in cell signaling. The assembly of large protein structures in health and disease is now viewed through the lens of phase separation and transition phenomena. What drives protein misfolding and aggregation? Or, more fundamentally, what hinders proteins from maintaining their native conformations, pushing them toward aggregation? Here, we explore the principles of protein folding, phase separation, and aggregation, which hinge on crucial events such as the reorganization of solvents, the chemical properties of amino acids, and their interactions with the environment. We focus on the dynamic shifts between functional and dysfunctional states of proteins and the conditions that promote protein misfolding, often leading to disease. By exploring these processes, we highlight potential therapeutic avenues to manage protein aggregation and reduce its harmful impacts on health.