Master of Arts (MA)
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).
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.
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