An Aryl Hydrocarbon Receptor from the Salamander Ambystoma mexicanum Exhibits Low Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin.
Structural features of the aryl hydrocarbon receptor (AHR) can underlie species- and population-specific differences in its affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These differences often explain variations in TCDD toxicity. Frogs are relatively insensitive to dioxin, and Xenopus AHRs bind TCDD with low affinity. Weak TCDD binding results from the combination of three residues in the ligand-binding domain: A354 and A370, and N325. Here we sought to determine whether this mechanism of weak TCDD binding is shared by other amphibian AHRs. We isolated an AHR cDNA from the Mexican axolotl (Ambystoma mexicanum). The encoded polypeptide contains identical residues at positions that confer low TCDD affinity to X. laevis AHRs (A364, A380, and N335), and homology modeling predicts they protrude into the binding cavity. Axolotl AHR bound one-tenth the TCDD of mouse AHR in velocity sedimentation analysis, and in transactivation assays, the EC50 for TCDD was 23 nM, similar to X. laevis AHR1β (27 nM) and greater than AHR containing the mouse ligand-binding domain (0.08 nM). Sequence, modeled structure, and function indicate that axolotl AHR binds TCDD weakly, predicting that A. mexicanum lacks sensitivity toTCDD toxicity. We hypothesize that this characteristic of axolotl and Xenopus AHRs arose in a common ancestor of the Caudata and Anura.
†Biology Department, Kenyon College, Gambier, Ohio 43022, United States.
Jenny
J
Shoots
‡Department of Earth and Environmental Sciences, University of Milano-Bicocca, 20126 Milan, Italy.
Domenico
D
Fraccalvieri
§Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543, United States.
Diana G
DG
Franks
∥Department of Environmental Toxicology, University of California-Davis, Davis, California 95616, United States.
Michael S
MS
Denison
§Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543, United States.
Mark E
ME
Hahn
‡Department of Earth and Environmental Sciences, University of Milano-Bicocca, 20126 Milan, Italy.
Laura
L
Bonati
†Biology Department, Kenyon College, Gambier, Ohio 43022, United States.
Wade H
WH
Powell
D000558:Ambystoma mexicanum / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D017930:Genes, Reporter; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D000072317:Polychlorinated Dibenzodioxins / Q000737:chemistry / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014982:Xenopus laevis / Q000235:genetics
C111855:6-formylindolo(3,2-b)carbazole; D002227:Carbazoles; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon