Degree Name
Master of Arts (MA)
Document Type
Thesis
School
Faculty of Arts and Sciences
Department
Biology
Date of Original Version
8-1-2019
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates a toxic response to many environmental contaminants. Cartilaginous fishes, due to gene duplication events, express 4 distinct AHR genes. Squalus acanthias AHR1 (SaAHR1) does not bind to typical AHR agonists, including dioxin-like chemicals (DLCs), whereas SaAHR2 binds to DLCs and subsequently upregulates genes containing dioxin responsive elements. Three-dimensional homology models were created based upon both human HIF1α and human HIF2α structural templates. These models yielded different secondary structural characteristics, most notably in the length of the β-strand on the C-terminal end of the ligand binding domain, which is centrally located in the antiparallel β-sheet that makes up a large portion of the ligand binding cavity. Residue A375 is located in a possible hinge area on this β-strand, and the mutation A375C would change this alanine residue in the nonbinding SaAHR1 to its analog in the DLC-binding SaAHR2, which may increase SaAHR1’s binding affinity to DLCs. The SaAHR1 also has a novel diproline motif comprising residues 379 and 380, located on the same β- strand as residue 375. This motif is not known to be found in any other AHR isoforms. Reversion of the diproline motif to proline-leucine, its analogous residues in SaAHR2, did not restore PCB 126 induced activation of a luciferase reporter gene. Epifluorescence microscopy using a heterologous expression system and an eGFP-SaAHR1 DNA construct revealed a nuclear localization unique to this isoform. Further characterization of this non-binding receptor could help to determine species-specific sensitivities to AHR agonists, especially in animals that are unavailable for direct experimentation (i.e.: endangered species).
Recommended Citation
Bock, Timothy, "Homology Modeling of the Squalus Acanthias AHR1 To Locate Structural Determinants of Function" (2019). Master's Theses, Dissertations, Graduate Research and Major Papers Overview. 307.
https://digitalcommons.ric.edu/etd/307
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