Heterotypic interactions between wild-type and mutant Cu, Zn superoxide dismutase : subunit swapping, metal migration, coaggregation, and cross seeding.

Dashnaw, Chad M., 1996-

Heterotypic interactions between wild-type and mutant Cu, Zn superoxide dismutase : subunit swapping, metal migration, coaggregation, and cross seeding.

dc.contributor.advisor	Shaw, Bryan Francis, 1976-
dc.creator	Dashnaw, Chad M., 1996-
dc.creator.orcid	0000-0002-7662-6611
dc.date.accessioned	2023-11-07T14:20:54Z
dc.date.available	2023-11-07T14:20:54Z
dc.date.created	2023-05
dc.date.issued	May 2023
dc.date.submitted	May 2023
dc.date.updated	2023-11-07T14:20:55Z
dc.description.abstract	Mutations in the Cu, Zn superoxide dismutase-1 (SOD1) gene accounts for approximately 10 % of familial amyotrophic lateral sclerosis (fALS). Interestingly, most SOD1 ALS-variants are dominantly inherited so that both homozygous and heterozygous individuals are affected. Furthermore, the dimeric nature of SOD1 allows for subunit exchange between wild-type (WT) and ALS-variant SOD1 creating a mixture of homo and heterodimeric SOD1. Despite this dominant inheritance, the heterotypic interactions between WT SOD1 and ALS-variant SOD1 remains largely unknown. In some cases (e.g., G85R, G93A, A4V), these heterotypic interactions seem to increase (or be required for) SOD1 toxicity and ALS pathogenesis. In this dissertation, I first investigate the heterodimerization of WT SOD1 and ALS-variant SOD1 in mismatched metalation states—where one subunit is metalated and the other is not—utilizing capillary electrophoresis (CE) and mass spectroscopy. Rates and free energies of subunit exchange were determined, and metal exchange was observed demonstrating that mutant or WT 4Zn-SOD1 could transfer Zn2+ to mutant or WT apo-SOD1. In the third chapter, I measure rates of SOD1 coaggregation between WT and five ALS-variants as well as the thermal stability of heterofibrils. Heterofibrils were observed to nucleate and propagate at slower rates compared to the respective homofibrils. Heterofibrils also showed increased thermal stability. Chapters four and five include projects dedicated to utilizing NHS esterStaudinger crosslinkers to measure the charge regulation in two proteins in a crowded environment as well as utilizing the lithophane data format as a tool for universal visualization to address the inaccessibility of STEM for people who are blind respectively.
dc.format.mimetype	application/pdf
dc.identifier.uri
dc.identifier.uri	https://hdl.handle.net/2104/12479
dc.language.iso	English
dc.rights.accessrights	No access – contact librarywebmaster@baylor.edu
dc.title	Heterotypic interactions between wild-type and mutant Cu, Zn superoxide dismutase : subunit swapping, metal migration, coaggregation, and cross seeding.
dc.type	Thesis
dc.type.material	text
thesis.degree.department	Baylor University. Dept. of Chemistry & Biochemistry.
thesis.degree.grantor	Baylor University
thesis.degree.name	Ph.D.
thesis.degree.program	Chemistry
thesis.degree.school	Baylor University