Advisor(s)
Stephen Aller
Suzanne Lapi
Committee Member(s)
Benjamin Larimer
Chad Petit
Robert Van Waardenburg
Todd Green
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Pharmacology and Toxicology
Date of Award
1-6-2025
Abstract
Pore forming toxins (PFTs) belonging to the ABC toxin complex (Tc) family are responsible for targeting and translocating toxins into target cells. ABC toxins consist of three separate subunits, each subunit providing a vital role in the cytotoxic mechanism of the Tc. The A subunit or TcA is the largest subunit of the complex and contains the binding domains and the translocation channel that perforates the membrane. The B subunit or TcB functions as a gated linker that forms a cocoon with the TcC which houses the toxic peptide and subsequently gets translocated through the TcB and TcA into the target cell. Many Tcs have been shown to target various insect species, shedding light onto the symbiotic relationship between the entomapathogenic nematodes that have benefited from the mutualistic relationship with the Tc secreting bacteria over time. Interestingly, Tcs show a broad range in targeting specificity between homologues, with some Tcs displaying pathogenicity to humans. The unique mechanism of Tcs has gained much interest over the past decade because it has the innate capability to carry shielded cargo, target cell surface receptors, and translocate peptides across the cell membrane. Efforts have been focused on obtaining the structure and understanding the binding and translocation mechanism that drives host tropism. Although much has been discovered about the structure and mechanism of ABC Tcs, there are many questions that still remain. In this work, I focus on the highly specific TcA from Xenorhabdus nematophilus, and test the hypothesis that the XptA2 structure and mechanism is similar to other structurally characterized TcAs with unique caveats responsible for differences in targeting specificity. Here I show the first high resolution structure of XptA2 and identify key components necessary for conformational change and toxin translocation. Additionally, we characterize Xn-XptA2 in relation to the other structurally solved TcAs and demonstrate the capability of this TcA to form a full complex with the TcB and TcC from Photorhabdus luminescens. Lastly, we highlight the potential biotechnology applications of XptA2 and other Tcs for utilization in transgenic plants and as a potential biological agent for site-directed cell death.
ProQuest ID
Recommended Citation
Martin, Cole Lorenza, "Understanding The Insecticidal Toxin Xpta2: A Shift In Toxin Complex Biology" (2025). All ETDs from UAB. 7287.
https://digitalcommons.library.uab.edu/etd-collection/7287
