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.

蛋白质聚集倾向是蛋白质组普遍且看似不可避免的特性。引人注目的是，蛋白质组的很大一部分是过饱和的，这意味着对于这些蛋白质，它们的天然构象不如聚集状态稳定。在这种条件下保持蛋白质组的完整性是不稳定的，并且需要消耗能量的蛋白质组的调节。那么为什么在漫长的进化时间尺度上聚集倾向保持在如此高的水平呢？在这里，我们认为天然状态和聚集状态的构象稳定性在热力学上是相关的，并且密码子的使用加强了这种相关性。因此，稳定蛋白质的折叠需要动力学控制以避免聚集，由聚集看门人提供。