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Stress response of the proteome

Määttä, Tomi

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Neurodegenerative diseases are often associated with the formation of protein aggregates. While this association is well established, the causal link between disease progression and protein aggregation is largely unknown. Protein aggregation processes have been mainly studied using reductionist experimental systems. However, it has recently become evident that protein aggregation and handling of protein aggregates is an actively controlled process in the cellular environment. Thus, it is crucial to study protein aggregation in a cellular context.

In this project, a mass spectrometry-based proteomics workflow was established to study protein aggregation, disaggregation and synthesis of endogenous human proteins in situ upon transient and non-lethal heat shock. To extend the scope, changes in thermal stability of proteins that remained soluble after heat shock were analyzed by thermal proteome profiling.

It was found that transient heat shock induced the aggregation of 300 mainly nuclear proteins enriched in intrinsically disordered regions, hydrophilic amino acids, high molecular weight and high isoelectric point. During recovery, most aggregated proteins became disaggregated. The disaggregation rates were found to correlate with the amount of intrinsically disordered regions in the proteins but not with other features enriched in aggregating proteins. In addition, larger loss of solubility after heat shock was counteracted by faster disaggregation. Protein synthesis had a global reversible halt after heat shock followed by an upregulation of heat shock proteins. Thermal stability was increased for soluble remnants of aggregating proteins, suggestive of a protective mechanism that prevents complete aggregation of unstable proteins. Furthermore, heat shock induced changes in thermal stability for proteins related to stress signaling, DNA binding and quality control.

Item Type: Dissertation
Supervisor: Savitski, Dr. Mikhail
Place of Publication: Heidelberg
Date of thesis defense: 16 September 2020
Date Deposited: 15 Oct 2020 12:39
Date: 2020
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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