Immature SOD1: protein folding, misfolding and aggregation
| dc.contributor.author | DEOL, HARMEEN | |
| dc.date.accessioned | 2023-01-25T15:07:14Z | |
| dc.date.available | 2024-01-26T05:50:06Z | |
| dc.date.issued | 2023-01-25 | |
| dc.date.submitted | 2023-01-24 | |
| dc.description.abstract | Protein misfolding and aggregation are hallmarks of many diseases, including amyotrophic lateral sclerosis (ALS). In familial ALS, aberrant self-association of mutant Cu,Zn-superoxide dismutase (SOD1) is implicated as a key contributor to disease. Mutations have the largest impacts on the stability of the most immature form of SOD1, the unmetallated, disulfide-reduced monomer (apoSH SOD1). Here we demonstrate that, despite the marginal stability of apoSH SOD1, aggregation is little correlated with the degree of protein unfolding, and multiple modes of aggregation occur, depending on the mutation and solution conditions. Additionally, we explore the local differences across apoSH SOD1 folded and unfolded structure and dynamics through chemical shift perturbations, both amide proton and nitrogen temperature coefficients, and peak shape analysis. These results provide new evidence that ALS-associated mutations promote the aggregation of apoSH SOD1 through multiple pathways and potentially through subtle differences in local structure and dynamics with broad implications for understanding mechanisms of protein self-association in disease and biotechnology. | en |
| dc.identifier.uri | http://hdl.handle.net/10012/19118 | |
| dc.language.iso | en | en |
| dc.pending | false | |
| dc.publisher | University of Waterloo | en |
| dc.subject | SOD1 | en |
| dc.title | Immature SOD1: protein folding, misfolding and aggregation | en |
| dc.type | Doctoral Thesis | en |
| uws-etd.degree | Doctor of Philosophy | en |
| uws-etd.degree.department | Chemistry | en |
| uws-etd.degree.discipline | Chemistry | en |
| uws-etd.degree.grantor | University of Waterloo | en |
| uws-etd.embargo.terms | 1 year | en |
| uws.contributor.advisor | Meiering, Elizabeth | |
| uws.contributor.affiliation1 | Faculty of Science | en |
| uws.peerReviewStatus | Unreviewed | en |
| uws.published.city | Waterloo | en |
| uws.published.country | Canada | en |
| uws.published.province | Ontario | en |
| uws.scholarLevel | Graduate | en |
| uws.typeOfResource | Text | en |