RESEARCH ARTICLE


Multiple Evolutionary Mechanisms Reduce Protein Aggregation



Joke Reumers1, 2, Frederic Rousseau*, 1, 2, Joost Schymkowitz*, 1, 2
1 VIB Switch Laboratory, Brussels, Belgium
2 Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium


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© 2009 Reumers et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; Tel: +321 6346227; Fax: 321 6347181; E-mail: frederic.rousseau@switch.vib-vub.be or joost.schymkowitz@switch.vib-vub.be


Abstract

The folding of polypeptides into stable globular protein structures requires protein sequences with a relatively high hydrophobicity and secondary structure propensity. These biophysical properties, however, also favor protein aggregation via the formation of intermolecular beta-sheets and, as a result, globular structure and aggregation are inextricable properties of protein polypeptides. Aggregates that are enriched in beta-sheet structures have been found in diseased tissues in association with at least twenty different human disorders and the effect of aggregation on protein function include simple loss-of-function but also often a gain of toxicity. Given both the ubiquity and the potentially lethal consequences of protein aggregation, negative selective pressure strongly minimizes aggregation. Various evolutionary strategies keep aggregation in check, including (1) the optimisation of the thermodynamic stability of the protein, which precludes aggregation by burial of the aggregation prone regions in solvent inaccessible regions of the structure, (2) segregation between folding nuclei and aggregation nuclei within a protein sequence, (3) the placement of so-called gatekeeper residues at the flanks of aggregating segments, that reduce the aggregation rate of (partially) unfolded proteins, and (4) molecular chaperones that target aggregation nucleating sequences directly, thereby further suppressing aggregation in a cellular environment. In this review we describe the intrinsic features built into protein sequence and structure that protect against aggregation.

Keywords: Amyloid, protein aggregation, protein aggregation and evolution, protein evolution, protein folding and aggregation, evolutionary pressure.