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Salt effects on protein folding behavior: revealing the molecular origins and limitation of Hofmeister theory
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-6048-6896
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-175630OAI: oai:DiVA.org:su-175630DiVA, id: diva2:1368397
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-12-12Bibliographically approved
In thesis
1. Protein stability and mobility in live cells: Revelation of the intracellular diffusive interaction organization mechanisms
Open this publication in new window or tab >>Protein stability and mobility in live cells: Revelation of the intracellular diffusive interaction organization mechanisms
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biochemical processes inside living cells take place in a confined and highly crowded environment. As such, macromolecular crowding, one of the most important physicochemical properties of cytoplasm, is an essential element of cell physiology. It not only gives rise to steric repulsion, but also promotes non-specific, transient, interactions (referred to as diffusive interactions) between molecules. Since diffusive interactions are a key way to achieving a highly organized intracellular environment, without such interactions, the cell is just “a bag of molecules”. Therefore, understanding how diffusive interactions modulate protein behavior in live cells is of fundamental importance for revealing the mechanisms of molecular recognition, as well as for understanding the cause of protein misfolding diseases.

This thesis focuses on how macromolecular crowding influences the stability and diffusive motions of proteins within living cells by modulating their diffusive interactions. First, we investigated the thermal stability of superoxide dismutase 1 (SOD1), a protein involved in the development of familial amyotrophic lateral sclerosis (ALS), in mammalian and E. coli cells. Intriguingly, the major thermodynamic consequence of macromolecular crowding is due not only to conventional steric repulsions, but primarily to the detailed chemical nature of the diffusive protein interactions in live cells. Secondly, we presented a mutational study of how these diffusive interactions influence the rotation of proteins in the mammalian and bacterial cytosol. The result is a quantitative description of the physicochemical code for the intracellular protein motion, showing that it depends critically on the surface details of protein and the type of the host cell as well. Thirdly, we characterized the impact of  intracellular protein concentration by altering the volume of E. coli cells by osmotic shock. The results obtained show that the intracellular diffusion of proteins is not determined by the chemical properties of the protein surface alone, but also by the frequency of concentration-dependent encounters. Moreover, it appears that eukaryotes and bacteria have achieved fidelity of biological processes through different evolutionary strategies. Overall, these observations have numerous implications for both functional protein design and deciphering the evolution of the surface characteristics of proteins.

Subsequently, we attempted to shed new light on the Hofmeister series, using protein-folding kinetics as observable. The results indicate that the Hofmeister series cannot be explained entirely by the traditional Kosmotropes/Chaotropes classification. Strong hetero-ion pairing cannot be ignored when trying to understand the effects of salts on protein salting-in and salting-out behaviors.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2019. p. 67
Keywords
diffusive interactions, macromolecular crowding, protein thermodynamic stability, protein mobility, in-cell NMR, Hofmeister series
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-175632 (URN)978-91-7797-931-9 (ISBN)978-91-7797-932-6 (ISBN)
Public defence
2019-12-19, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript.

Available from: 2019-11-26 Created: 2019-11-07 Last updated: 2019-11-19Bibliographically approved

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