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The role of water mobility in protein misfolding

View ORCID ProfileAmberley D. Stephens, View ORCID ProfileJohanna Kölbel, Rani Moons, View ORCID ProfileMichael T. Ruggerio, View ORCID ProfileNajet Mahmoudi, View ORCID ProfileTalia A. Shmool, View ORCID ProfileThomas M. McCoy, View ORCID ProfileDaniel Nietlispach, View ORCID ProfileAlexander F. Routh, View ORCID ProfileFrank Sobott, View ORCID ProfileJ. Axel Zeitler, View ORCID ProfileGabriele S. Kaminski Schierle
doi: https://doi.org/10.1101/2021.01.06.425575
Amberley D. Stephens
1Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
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Johanna Kölbel
1Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
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Rani Moons
2Department of Chemistry, University of Antwerp, Belgium
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Michael T. Ruggerio
1Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
3Department of Chemistry, University of Vermont, USA
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Najet Mahmoudi
4ISIS, STFC, Rutherford Appleton Laboratory, UK
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Talia A. Shmool
1Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
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Thomas M. McCoy
1Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
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Daniel Nietlispach
5Department of Biochemistry, University of Cambridge, UK
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Alexander F. Routh
1Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
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Frank Sobott
6The Astbury Centre for Structural Molecular Biology, University of Leeds, UK
2Department of Chemistry, University of Antwerp, Belgium
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J. Axel Zeitler
1Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
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Gabriele S. Kaminski Schierle
1Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
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  • For correspondence: gsk20@cam.ac.uk
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Abstract

The propensity for intrinsically disordered proteins to aggregate is heavily influenced by their surrounding environment. Here, we show that the mobility of the surrounding water molecules directly influences the aggregation rate of α-synuclein (aSyn), a protein associated with Parkinson’s disease. We observe that the addition of NaCl reduces the mobility of water, while addition of CsI increases the mobility of water. In turn, this reduces and increases the mobility of aSyn, respectively, given the change in strength and lifetime of the intermolecular forces. The reduction of aSyn mobility in the presence of NaCl ions leads to increased aggregation rates, which may be due to aggregation-competent conformations being stable for longer, thereby increasing the likelihood of establishing interactions between two adjacent monomers. In contrast, aSyn is more mobile when CsI is dissolved in the aqueous phase which leads to a reduction of successful monomeric interactions. We thus highlight the importance of the surrounding environment and describe how ion content can influence water mobility and the misfolding rate of amyloidogenic proteins, such as aSyn. By modulating the cellular environment to increase water mobility or finding small molecules to increase protein dynamics, new therapeutic targets may be found.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 09, 2021.
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The role of water mobility in protein misfolding
Amberley D. Stephens, Johanna Kölbel, Rani Moons, Michael T. Ruggerio, Najet Mahmoudi, Talia A. Shmool, Thomas M. McCoy, Daniel Nietlispach, Alexander F. Routh, Frank Sobott, J. Axel Zeitler, Gabriele S. Kaminski Schierle
bioRxiv 2021.01.06.425575; doi: https://doi.org/10.1101/2021.01.06.425575
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The role of water mobility in protein misfolding
Amberley D. Stephens, Johanna Kölbel, Rani Moons, Michael T. Ruggerio, Najet Mahmoudi, Talia A. Shmool, Thomas M. McCoy, Daniel Nietlispach, Alexander F. Routh, Frank Sobott, J. Axel Zeitler, Gabriele S. Kaminski Schierle
bioRxiv 2021.01.06.425575; doi: https://doi.org/10.1101/2021.01.06.425575

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