title: Structural hot spots for the solubility of globular proteins.
abstract: Natural selection shapes protein solubility to physiological requirements and recombinant applications that require higher protein concentrations are often problematic. This raises the question whether the solubility of natural protein sequences can be improved. We here show an anti-correlation between the number of aggregation prone regions (APRs) in a protein sequence and its solubility, suggesting that mutational suppression of APRs provides a simple strategy to increase protein solubility. We show that mutations at specific positions within a protein structure can act as APR suppressors without affecting protein stability. These hot spots for protein solubility are both structure and sequence dependent but can be computationally predicted. We demonstrate this by reducing the aggregation of human α-galactosidase and protective antigen of Bacillus anthracis through mutation. Our results indicate that many proteins possess hot spots allowing to adapt protein solubility independently of structure and function.
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Ashok
authors.initials: A
authors.lastname: Ganesan
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Siekierska
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.|Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel, Belgium.
authors.forename: Jacinte
authors.initials: J
authors.lastname: Beerten
authors.affiliation: KU Leuven, Laboratory for Structural Neurobiology, Department of Cellular and Molecular Medicine, Herestraat 49, PB 601, B-3000 Leuven, Belgium.
authors.forename: Marijke
authors.initials: M
authors.lastname: Brams
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Van Durme
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: De Baets
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Rob
authors.initials: R
authors.lastname: Van der Kant
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Gallardo
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Meine
authors.initials: M
authors.lastname: Ramakers
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Tobias
authors.initials: T
authors.lastname: Langenberg
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: Wilkinson
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: De Smet
authors.affiliation: KU Leuven, Laboratory for Structural Neurobiology, Department of Cellular and Molecular Medicine, Herestraat 49, PB 601, B-3000 Leuven, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Ulens
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), 3000 Leuven, Belgium.|KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine, Herestraat 49, PB 802, 3000 Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
mesh_terms: D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D004591:Electrophoresis, Polyacrylamide Gel; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D055550:Protein Stability; D012995:Solubility; D000519:alpha-Galactosidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D000519:alpha-Galactosidase