A Genome-Wide Sequence–Structure Analysis Suggests Aggregation Gatekeepers Constitute an Evolutionary Constrained Functional Class

• Aggregation is inhibited by the enrichment of gatekeepers at the flanks of the APRs
• Gatekeepers destabilize the protein structure but are under selective conservation
• Gatekeepers are a functional class dedicated to the control of protein aggregation
• Aggregation is minimized by an evolutionary constrained functional class, namely gatekeepers.

Protein aggregation is geared by aggregation-prone regions that self-associate by β-strand interactions. Charged residues and prolines are enriched at the flanks of aggregation-prone regions resulting in decreased aggregation. It is still unclear what drives the overrepresentation of these “aggregation gatekeepers”, that is, whether their presence results from structural constraints determining protein stability or whether they constitute a bona fide functional class selectively maintained to control protein aggregation. As functional residues are typically conserved regardless of their cost to protein stability, we compared sequence conservation and thermodynamic cost of these residues in 2659 protein families in Escherichia coli. Across protein families, we find gatekeepers to be under strong selective conservation while at the same time representing a significant thermodynamic cost to protein structure. This finding supports the notion that aggregation gatekeepers are not structurally determined but evolutionary selected to control protein aggregation.

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