How evolutionary pressure against protein aggregation shaped chaperone specificity.

As protein aggregation is potentially lethal, control of protein conformation by molecular chaperones is essential for cellular organisms. This is especially important during protein expression and translocation, since proteins are then unfolded and therefore most susceptible to form non-native interactions. Using TANGO, a statistical mechanics algorithm to predict protein aggregation, we here analyse the aggregation propensities of 28 complete proteomes. Our results show that between 10% and 20% of the residues in these proteomes are within aggregating protein segments and that this represents a lower limit for the aggregation tendency of globular proteins. Further, we show that not only evolution strongly pressurizes aggregation downwards by minimizing the amount of strongly aggregating sequences but also by selectively capping strongly aggregating hydrophobic protein sequences with arginine, lysine and proline. These residues are strongly favoured at these positions as they function as gatekeepers that are most efficient at opposing aggregation. Finally, we demonstrate that the substrate specificity of different unrelated chaperone families is geared by these gatekeepers. Chaperones face the difficulty of having to combine substrate affinity for a broad range of hydrophobic sequences and selectivity for those hydrophobic sequences that aggregate most strongly. We show that chaperones achieve these requirements by preferentially binding hydrophobic sequences that are capped by positively charged gatekeeper residues. In other words, targeting evolutionarily selected gatekeepers allows chaperones to prioritize substrate recognition according to aggregation propensity.