Protein disulfide isomerase (PDI) is an endoplasmic reticulum (ER)-resident chaperone with oxidoreductase and isomerase activity. Unique to its normal function, PDI also appears to disassemble the A1 subunits of cholera toxin (CT) and heat-labile enterotoxin (LT). It does so using an unfolding mechanism that knocks the catalytic A1 subunit away from the rest of the holotoxin. Release of the A1 subunit is linked to the diarrheal diseases caused by V. cholerae and enterotoxicogenic E. coli (ETEC). Due to the previously established difference in disease potency between CT and LT, we investigated and established a distinction between the two toxins in their efficacy of disassembly by PDI. We further identified four amino acid differences between the CTA2 and LTA2 linkers, which connect the A1 and cell-binding B subunits of both toxins, as the basis for this difference. We believe these four amino acids result in changes to holotoxin architecture that lead to antiparallel binding of PDI to LT as opposed to CT, which translates to a loss of momentum for the physical disassembly of LT. We have shown this through algorithmic simulations of the binding event between PDI and either CT or LT. We hypothesized the unfolding mechanism of PDI, which dislodges the A1 subunit of both CT and LT, can also break down neurotoxic aggregates of β-Amyloid (AB) and α-Synuclein (AS). PDI is known to inhibit the aggregation of the amyloid proteins. We demonstrated here that PDI could also reverse oligomeric and post-oligomeric aggregates of AB and AS, respectively. Our work sheds light on the specifics of PDI's novel physical mechanism as well as introduce it as a possible therapeutic for both Alzheimer's and Parkinson's disease due to its unique ability to disaggregate early fibrillar structures of AS and AB proteins.
| Identifer | oai:union.ndltd.org:ucf.edu/oai:stars.library.ucf.edu:etd2023-1000 |
| Date | 01 January 2023 |
| Creators | Serrano, Albert A |
| Publisher | STARS |
| Source Sets | University of Central Florida |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Graduate Thesis and Dissertation 2023-2024 |
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