Article pubs.acs.org/Biomac
N‑Terminal Protein Tails Act as Aggregation Protective Entropic Bristles: The SUMO Case Ricardo Graña-Montes,† Patrizia Marinelli,† David Reverter, and Salvador Ventura* Institut de Biotecnologia i Biomedicina and Departament de Bioquimica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain S Supporting Information *
ABSTRACT: The formation of β-sheet enriched amyloid fibrils constitutes the hallmark of many diseases but is also an intrinsic property of polypeptide chains in general, because the formation of compact globular proteins comes at the expense of an inherent sequential aggregation propensity. In this context, identification of strategies that enable proteins to remain functional and soluble in the cell has become a central issue in chemical biology. We show here, using human SUMO proteins as a model system, that the recurrent presence of disordered tails flanking globular domains might constitute yet another of these protective strategies. These short, disordered, and highly soluble protein segments would act as intramolecular entropic bristles, reducing the overall protein intrinsic aggregation propensity and favoring thus the attainment and maintenance of functional conformations.
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INTRODUCTION Protein misfolding and aggregation into β-sheet enriched amyloid-like structures are associated with a large set of human disorders, including Alzheimer’s disease, diabetes, and some types of cancer.1−4 However, the adoption of cytotoxic amyloid-like conformations is not restricted to disease-linked proteins and seems to constitute a generic property of polypeptide chains,5,6 likely because the noncovalent contacts that stabilize native structures resemble those leading to the formation of amyloids.7 Indeed, a majority of proteins contain at least one and often several aggregation-promoting sequences,8,9 in many cases buried in the hydrophobic core of the native structure. Therefore, productive protein folding and deleterious aggregation are continuously competing in the cell. Because the formation of compact globular proteins comes at the expense of an inherent sequential aggregation propensity, identification of the strategies that enable proteins to remain functional and soluble in the cell is a central issue in biology.10 Organisms have evolved different mechanisms to survey and minimize side aggregation reactions,11−15 including sophisticated and highly conserved protein quality control machineries.16,17 In addition, during the course of evolution, proteins have adopted negative design strategies to prevent or diminish their intrinsic propensity to aggregate, by incorporating β-sheet breakers at structurally critical positions,18,19 avoiding the presence of β-strands on the edge of protein structures20 or placing gatekeeper residues at the flanks of aggregation-prone segments.8 It has been recently suggested that the recurrent presence of disordered segments adjacent to folded domains in proteomes might be yet another strategy evolved to overcome aggregation.21 Random movements of these tails around the © 2014 American Chemical Society
point of attachment to the folded domain would sweep out a large area in space, acting thus as entropic bristles (EB).22,23 Recently, the ability of long and highly disordered tails, either natural or artificial, to act as EB was tested experimentally by fusing them to different target proteins and expressing the fusions recombinantly in bacteria. Proteins fused to these EB were significantly more soluble than their natural counterparts.22 Several evidences indicate that disordered terminal tails might also play an antiaggregational effect in the context of natural proteins. In this way, it has been shown that the disordered C-terminal region of NEIL1, a human homologue of Escherichia coli DNA glycosylase endonuclease VIII, is necessary for its soluble recombinant expression.24 A similar role has been proposed for the highly charged and disordered C-terminal tail of α-synuclein in the context of α-synuclein-GST fusions.25 SUMO belongs to the ubiquitin-like (Ubl) protein family. The members of the Ubl family are small size (
