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Structural hot spots for the solubility of globular proteins

Author

Listed:
  • Ashok Ganesan

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Aleksandra Siekierska

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Jacinte Beerten

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory
    Vrije Universiteit Brussel)

  • Marijke Brams

    (KU Leuven, Laboratory for Structural Neurobiology)

  • Joost Van Durme

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    Vrije Universiteit Brussel)

  • Greet De Baets

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Rob Van der Kant

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Rodrigo Gallardo

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Meine Ramakers

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Tobias Langenberg

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Hannah Wilkinson

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Frederik De Smet

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Chris Ulens

    (KU Leuven, Laboratory for Structural Neurobiology)

  • Frederic Rousseau

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

  • Joost Schymkowitz

    (VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB)
    KU Leuven, Switch Laboratory)

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.

Suggested Citation

  • 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, 2016. "Structural hot spots for the solubility of globular proteins," Nature Communications, Nature, vol. 7(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10816
    DOI: 10.1038/ncomms10816
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    Cited by:

    1. Nikolaos Louros & Meine Ramakers & Emiel Michiels & Katerina Konstantoulea & Chiara Morelli & Teresa Garcia & Nele Moonen & Sam D’Haeyer & Vera Goossens & Dietmar Rudolf Thal & Dominique Audenaert & F, 2022. "Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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