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Ligand Selectivity and Evolutionary Divergence

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Ligand Selectivity and Evolutionary Divergence The Pennsylvania State University The Graduate School Department of Biochemistry, Microbiology, and Molecular Biology LIGAND SELECTIVITY AND EVOLUTIONARY DIVERGENCE OF THE HUMAN ARYL HYDROCARBON RECEPTOR A Dissertation in Biochemistry, Microbiology, and Molecular Biology by Troy D. Hubbard ©2017 Troy Hubbard Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2017 ii The dissertation of Troy D. Hubbard was reviewed and approved* by the following: Gary H. Perdew John T. and Paige S. Smith Professor in Agricultural Sciences Director of the Center for Molecular Toxicology and Carcinogenesis Dissertation Advisor Chair of Committee Edward G. Dudley Associate Professor of Food Science Andrew D. Patterson Associate Professor of Molecular Toxicology Jeffrey M. Peters Distinguished Professor of Molecular Toxicology & Carcinogenesis Ming Tien Professor of Biochemistry Scott Selleck Professor and Department Head of Biochemistry and Molecular Biology *Signatures are on file in the Graduate School iii ABSTRACT The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor of the basic region helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) homology super family. The AHR was first identified as the primary mediator of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity and regulator of xenobiotic metabolism. Further investigation revealed AHR possesses a promiscuous ligand binding domain (LBD) that is able to bind to an array of exogenous compounds, such as polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs). Following ligand-binding, the AHR forms a functional heterodimeric transcription factor with AHR nuclear translocator (ARNT) and regulates expression of target genes via binding of dioxin response elements (DREs) within their promoters. The physiological activity of the AHR has expanded to include pivotal roles within immune regulation, mucosal barrier function, cell cycle progression, organogenesis, circadian rhythm, and cellular differentiation pathways. However, these functions often require the ligand activated form of the receptor and are known to occur in the absence of exogenous ligand. This finding led to the premise and eventual characterization of endogenous AHR ligands. The catabolism of the amino acid tryptophan by commensal microorganisms, endogenous enzymes, and radical oxidation is a known source of numerous AHR ligands. The studies presented in here build upon previously published data establishing microbial metabolism as a reservoir of endogenous ligand production. In our research we have identified the microbial tryptophan metabolite indole as a human AHR selective agonist through SAR studies and in silico modeling of AHR-ligand molecular docking. In silico molecular docking models support observations of differential indole responsiveness between species through a unique bi-molecular (2:1) binding stoichiometry that is sterically permissive within the human iv AHR, but not its mouse homolog. The capacity for host cells to sense microbial indole through the AHR may be paramount to the establishment of an inter-kingdom signaling pathway that affects maintenance of intestinal homeostasis. Molecular functionalities of the AHR, such as heterodimerization with ARNT and binding of DREs, are conserved among vertebrate and invertebrate species. However, ligand specificity of the AHR can vary between species. Comparative studies have shown that the human AHR displays reduced binding capacity with regard to prototypical PAH agonists when compared to rodent homologs. Such differences suggest that divergence of the AHR ligand binding domain (LBD) structure during the course of mammalian evolution facilitated interspecies variation in ligand selectivity. Here we present evidence supporting the hypothesis that selective desensitization of the human AHR to PAHs arose during speciation of Homo sapiens. Interspecies AHR analyses, through utilization of ligand binding assay, DNA binding assay, and AHR-dependent gene expression identified a single amino acid substitution (A381V) as the determinant in reduced PAH affinity exhibited by H. sapiens relative to their Homo neanderthalensis (Neanderthal) and primate counterparts. Notably, H. sapiens AHR responsiveness to endogenous ligands derived from tryptophan and indole metabolism remains unperturbed. These findings reveal that a functionally significant mutation in the AHR occurred uniquely in humans that would attenuate the response to many environmental pollutants, including chemicals present in smoke. v TABLE OF CONTENTS LIST OF FIGURES ................................................................................................................... viii LIST OF TABLES ........................................................................................................................ x ABBREVIATIONS ...................................................................................................................... xi ACKNOWLEDGEMENTS ...................................................................................................... xiv CHAPTER 1: INTRODUCTION ................................................................................................ 1 1.1 DISCOVERY OF THE ARYL HYDROCARBON RECEPTOR ........................................ 2 1.2 AHR BASIC-HELIX-LOOP-HELIX PERN-ARNT-SIM HOMOLOGY .......................... 4 1.3 THE CLASSICAL AHR SIGNALING PATHWAY ........................................................... 7 1.4 THE ROLE OF AHR CYTOPLASMIC CHAPERONE PROTEINS ................................ 10 HSP90 .................................................................................................................................... 10 XAP2 ..................................................................................................................................... 12 P23 ......................................................................................................................................... 15 1.5 AHR REGULATION OF TRANSCRIPTION AHR TRANSLOCATION ....................... 15 ARNT .................................................................................................................................... 16 AHR-ARNT HETERODIMERIZATION AND DNA-BINDING ....................................... 17 AHR REGULATION OF CYP1A1 TRANSCRIPTION ...................................................... 18 ADDITIONAL MECHANISMS OF AHR TRANSCRIPTIONAL REGULATION .......... 19 DOWN-REGULATION OF AHR-DEPENDENT SIGNALING ........................................ 21 1.6 PHYSIOLOGICAL IMPLICATIONS OF THE AHR KNOCKOUT MOUSE ................. 23 AHR IMPLICATIONS IN IMMUNE FUNCTION ............................................................. 23 AHR AND INTESTINAL HOMEOSTASIS ........................................................................ 24 vi AHR IMPLICATIONS IN CELL CYCLE PROGRESSION AND CANCER .................... 26 1.7 AHR LIGANDS .................................................................................................................. 28 EXOGENOUS AHR AGONISTS ......................................................................................... 29 B(a)P METABOLISM .......................................................................................................... 31 ENDOGENOUS AHR LIGANDS ........................................................................................ 35 DIETARY AHR LIGANDS .................................................................................................. 35 MICROBIOTA DERIVED AHR LIGANDS ....................................................................... 40 HOST BIOACTIVATION OF INDOLE .............................................................................. 46 HOST TRYPTOPHAN METABOLISM GENERATES AHR LIGANDS.......................... 48 UV-CATALZYED GENERATION OF AHR LIGANDS ................................................... 54 1.8 THE AHR LIGAND BINDING DOMAIN ........................................................................ 55 1.9 INTERSPECIES DIFFERENCES IN AHR LIGAND SELECTIVITY AND TRANSCRIPTIONAL ACTIVITY .......................................................................................... 56 1.10 OVERVIEW AND SIGNIFIGANCE ............................................................................... 58 CHAPTER 2 : UNIQUE BINDING CHARACTERISTICS AND ADAPTATION OF THE HUMAN ARYL HYDROCARBON RECEPTOR TO SENSE MICROBIOTA-DERIVED INDOLES..................................................................................................................................... 60 2.1 ABSTRACT ........................................................................................................................ 61 2.2 INTRODUCTION ............................................................................................................... 62 2.3 MATERIALS AND METHODS ........................................................................................ 65 2.4 RESULTS ............................................................................................................................ 72 2.5 DISCUSSION ..................................................................................................................... 99 vii CHAPTER 3: DIVERGENT AH RECEPTOR LIGAND SELECTIVITY DURING HOMININ EVOLUTION ........................................................................................................ 106 3.1 ABSTRACT .....................................................................................................................
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