Structural hot spots for the solubility of globular proteins

• DOI: 10.1038/ncomms10816
• Publication Date: 2016-02-24T11:02:01Z
• Authors: Ashok Ganesan; Aleksandra Siekie...; Jacinte Beerten; Marijke Brams; Joost Van Durme; Greet De Baets; Rob Van der Kant; Rodrigo Gallardo; Meine Ramakers; Tobias Langenberg; Hannah Wilkinson; Frederik De Smet; Chris Ulens; Frederic Rousseau; Joost Schymkowitz
• Keywords: Antigens, Bacterial; 0303 health sciences; Protein Stability; Science; Q; Bacterial Toxins; Blotting, Western; Crystallography, X-Ray; Article; 03 medical and health sciences; Solubility; Cell Line, Tumor; alpha-Galactosidase; Mutation; Chromatography, Gel; Humans; Electrophoresis, Polyacrylamide Gel; Amino Acid Sequence; HeLa Cells

AbstractNatural 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.