title: A genome-wide sequence-structure analysis suggests aggregation gatekeepers constitute an evolutionary constrained functional class.
abstract: 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.
authors.affiliation: Switch Laboratory, Flanders Institute for Biotechnology (Vlaams Instituut voor Biotechnologie), 3000 Leuven, Belgium; Switch Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, 3000 Leuven, Belgium; Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: De Baets
authors.affiliation: Switch Laboratory, Flanders Institute for Biotechnology (Vlaams Instituut voor Biotechnologie), 3000 Leuven, Belgium; Switch Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, 3000 Leuven, Belgium; Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Van Durme
authors.affiliation: Switch Laboratory, Flanders Institute for Biotechnology (Vlaams Instituut voor Biotechnologie), 3000 Leuven, Belgium; Switch Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Frederic.Rousseau@switch.vib-kuleuven.be.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Switch Laboratory, Flanders Institute for Biotechnology (Vlaams Instituut voor Biotechnologie), 3000 Leuven, Belgium; Switch Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Joost.Schymkowitz@switch.vib-kuleuven.be.
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
mesh_terms: D017124:Conserved Sequence; D004926:Escherichia coli / Q000737:chemistry* / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011489:Protein Denaturation; D055503:Protein Multimerization; D055550:Protein Stability; D013816:Thermodynamics
chemical_list: D029968:Escherichia coli Proteins
keywords: evolution; gatekeepers; protein aggregation; thermodynamic stability