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In-cell destabilization of SOD1 induced by surface-exposed histidines
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-9616-6552
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0003-1967-3224
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology Biophysics Neurosciences Physical Chemistry
Research subject
Biochemistry; Biophysics; Physical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-187926OAI: oai:DiVA.org:su-187926DiVA, id: diva2:1510789
Available from: 2020-12-16 Created: 2020-12-16 Last updated: 2022-02-25Bibliographically approved
In thesis
1. Biophysical chemistry of the ALS-associated protein SOD1: Implications for folding, aggregation and in-cell behaviour
Open this publication in new window or tab >>Biophysical chemistry of the ALS-associated protein SOD1: Implications for folding, aggregation and in-cell behaviour
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biophysical chemistry deals with the structural behavior, properties and molecular function of biological macromolecules. A long-standing challenge is here to establish how these macromolecular features change upon transfer from simplified conditions in vitro to the crowded and molecularly complex environment of live cells.  

This thesis focuses on establishing a general overview of the structural behavior and interaction properties of the ALS-associated protein superoxide dismutase 1 (SOD1) in its natural cellular environment. Importantly, SOD1 constitutes also a multifaceted model system for the yet poorly understood mechanism of protein-aggregation disease, since it is readily amenable to protein-engineering analysis. The focus is on (i) SOD1 folding, (ii) the modulation of the SOD1 properties induced by intracellular interactions and (iii) the process of SOD1 fibrillation, all of which central to the understanding of the ALS disease mechanism. First, we investigate the biophysical role of the disordered catalytic loops in the apoSOD1 monomer, what is identified as the primary aggregation precursor. The results show that these loops play a pivotal role in modulation the apoSOD1 stability due to the generic Flory-entropy penalty, shedding new light to why this species is biased to be aggregation prone. Second, we target the diffusive interactions between SOD1 and the crowded intracellular environment by in-cell NMR. Our findings are that both the rotational tumbling and in-cell stability are controlled by basic physicochemical rules relating to the SOD1 surface properties. Finally, we analyze the kinetics of the SOD1-aggregation behavior in vitro. The observations confirm that the disordered SOD1 loops indeed accelerate the aggregation process because of their penalty to the apo state stability and show, additionally, that they influence the fibril stability.

The physicochemical cues exposed by this thesis work provide not only fundamental clues to our understanding of protein properties, but shed also new light on disease-promoting properties ALS-associated protein SOD1.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2021. p. 67
Keywords
SOD1 ALS folding in-cell NMR aggregation
National Category
Biochemistry and Molecular Biology Biophysics Physical Chemistry
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-187932 (URN)978-91-7911-394-0 (ISBN)978-91-7911-395-7 (ISBN)
Public defence
2021-02-12, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B or online via Zoom, public link is available at the department website, Stockholm, 10:00 (English)
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Available from: 2021-01-20 Created: 2020-12-16 Last updated: 2022-02-25Bibliographically approved

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Yang, FanHuabing, WangXin, MuLogan, DerekLeeb, SarahDanielsson, JensOliveberg, Mikael

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