Protein structure and aggregation: a marriage of necessity ruled by aggregation gatekeepers.

Protein aggregation propensity is a pervasive and seemingly inescapable property of proteomes. Strikingly, a significant fraction of the proteome is supersaturated, meaning that, for these proteins, their native conformation is less stable than the aggregated state. Maintaining the integrity of a proteome under such conditions is precarious and requires energy-consuming proteostatic regulation. Why then is aggregation propensity maintained at such high levels over long evolutionary timescales? Here, we argue that the conformational stability of the native and aggregated states are correlated thermodynamically and that codon usage strengthens this correlation. As a result, the folding of stable proteins requires kinetic control to avoid aggregation, provided by aggregation gatekeepers. These unique residues are evolutionarily selected to kinetically favor native folding, either on their own or by coopting chaperones.