Structural hot spots for the solubility of globular proteins

Ashok Ganesan, Aleksandra Siekierska, 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 () and Joost Schymkowitz ()
Additional contact information
Ashok Ganesan: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Aleksandra Siekierska: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Jacinte Beerten: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Marijke Brams: KU Leuven, Laboratory for Structural Neurobiology
Joost Van Durme: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Greet De Baets: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Rob Van der Kant: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Rodrigo Gallardo: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Meine Ramakers: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Tobias Langenberg: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Hannah Wilkinson: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Frederik De Smet: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Chris Ulens: KU Leuven, Laboratory for Structural Neurobiology
Frederic Rousseau: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
Joost Schymkowitz: VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10816

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