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Identification of Novel Ligands and Structural Requirements for Heterodimerization of the Liver X Receptor Alpha

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Identification of Novel Ligands and Structural Requirements for Heterodimerization of the Liver X Receptor Alpha Wright State University CORE Scholar Browse all Theses and Dissertations Theses and Dissertations 2017 Identification of Novel Ligands and Structural Requirements for Heterodimerization of the Liver X Receptor Alpha Shimpi Bedi Wright State University Follow this and additional works at: https://corescholar.libraries.wright.edu/etd_all Part of the Biomedical Engineering and Bioengineering Commons Repository Citation Bedi, Shimpi, "Identification of Novel Ligands and Structural Requirements for Heterodimerization of the Liver X Receptor Alpha" (2017). Browse all Theses and Dissertations. 1743. https://corescholar.libraries.wright.edu/etd_all/1743 This Dissertation is brought to you for free and open access by the Theses and Dissertations at CORE Scholar. It has been accepted for inclusion in Browse all Theses and Dissertations by an authorized administrator of CORE Scholar. For more information, please contact [email protected]. IDENTIFICATION OF NOVEL LIGANDS AND STRUCTURAL REQUIREMENTS FOR HETERODIMERIZATION OF THE LIVER X RECEPTOR ALPHA A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy By SHIMPI BEDI M.S., Wright State University, 2009 B.S., Panjab University, 1988 2017 Wright State University COPYRIGHT BY SHIMPI BEDI 2017 WRIGHT STATE UNIVERSITY GRADUATE SCHOOL April 25, 2017 I HEREBY RECOMMEND THAT THE DISSERTATION PREPARED UNDER MY SUPERVISION BY Shimpi Bedi ENTITLED Identification of Novel Ligands and Requirements for Heterodimerization of the Liver X Receptor Alpha BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Doctor of Philosophy. _____________________________ Stanley Dean Rider, Jr., Ph.D. Dissertation Director _____________________________ Mill W. Miller, Ph.D. Director, Biomedical Sciences Ph.D. Program _____________________________ Robert E. W. Fyffe, Ph.D. Vice President for Research and Committee on Dean of the Graduate School Final Examination ______________________________________ Stanley Dean Rider, Jr., Ph.D. ______________________________________ Jerry Alter., Ph.D. ______________________________________ Lawrence J. Prochaska, Ph.D. ______________________________________ Katherine Excoffon, Ph.D. ______________________________________ Nicholas V. Reo, Ph.D. _____________________________________ J. Ashot Kozak, Ph.D. ABSTRACT Bedi, Shimpi Ph.D., Biomedical Sciences Ph.D. program, Department of Biochemistry and Molecular Biology, Wright State University, 2017. Identification of novel ligands and structural requirements for heterodimerization of the liver X receptor alpha. LXRs, LXRα (NR1H3) and LXRβ (NR1H2), are ligand-activated transcription factors that are members of the nuclear receptor superfamily. Oxysterols and nonsteroidal synthetic compounds bind directly to LXRs and influence the expression of LXR dependent genes. The use of murine models and LXR-selective agonists have established the important role of LXRs as sterol sensors that govern the absorption, transport, and catabolism of cholesterol. Upon activation, these receptors have been shown to increase reverse cholesterol transport from the macrophage back to the liver to aid in the removal of excess cholesterol. Not surprisingly, LXR dysregulation is a feature of several human diseases, including metabolic syndrome. Due to their roles in the regulation of lipid and cholesterol metabolism, LXRs are potentially attractive pharmaceutical targets. As ligand binding and dimerization play pivotal roles in modulating LXR activity, the identification of novel ligands and requirements for LXR dimerization can potentially aid the drug development process. Herein, using a variety of biophysical assays, including fluorescence based assays coupled with in silico molecular modeling, I have identified medium chain fatty acids and/or their metabolites as the novel endogenous agonists of LXRα. There is mounting evidence that ligand induced dimerization regulates the transcriptional output of nuclear receptors. Thus, it is important to identify factors that iv modulate protein-protein interactions. This work demonstrated that (a) LXRα binds PPARα with a high affinity (low nanomolar concentration), (b) ligands for LXRα alter the binding dissociation constant values of LXRα-PPARα interaction, and (c) ligand binding induces conformational changes in the dimer secondary structure. Furthermore, site-directed mutagenesis investigated the strength of individual contributions of residues located in the ligand binding domain to dimerization and transactivation properties of LXRα. Data herein highlight the importance of hydrophobic interactions and salt bridges at the interface, and suggest that key interface residues are required for the ligand- dependent activation of LXRα in a promoter specific manner. Mutagenesis of LXRα L414 to an arginine revealed the importance of this site in dimerization, specifically with RXRα. This work showed that this particular mutation specifically abolished dimerization with RXRα. Taken together, this study provided insights into the functional roles of fatty acids as novel LXRα ligands and the effects mutations may have in modulating molecular interactions and activity profile of LXRα. v TABLE OF CONTENTS INTRODUCTION ............................................................................................................1 Metabolic syndrome .....................................................................................................1 Liver X receptor (LXR) ................................................................................................6 LXR structure and function ..........................................................................................6 LXRα isoforms .......................................................................................................6 LXRα target genes .................................................................................................6 LXR-RXR dimerization .........................................................................................6 Domain structure ....................................................................................................8 Ligand binding domain (LBD) ...............................................................................9 Crystal structure of LXRα-RXRβ ........................................................................10 Agonist binding to the LBD ...................................................................................9 Ligand binding mode ............................................................................................10 Ligands of LXRα .......................................................................................................14 Heterodimerization of LXRα .....................................................................................16 Binding partners of LXRα ....................................................................................16 LXRα interface .....................................................................................................17 Identification of residues required for dimer formation .......................................18 Sequence alignment of LBDs ...............................................................................20 Solvent accessibility of LXRα LBD residues ......................................................21 vi TABLE OF CONTENTS (continued) Regulation of LXRα ..................................................................................................22 Function of LXRα .....................................................................................................22 Reverse cholesterol transport ..............................................................................26 Cholesterol synthesis ..........................................................................................26 Cholesterol uptake ..............................................................................................27 Intestinal cholesterol absorption .........................................................................27 Fecal neutral sterol excretion via intestine..........................................................27 Apolipoprotein-mediated lipid efflux via ABCA1 .............................................28 HDL-cholesterol and ApoA1 ..............................................................................28 Animal Models of LXRα ............................................................................................29 LDL and HDL ............................................................................................................30 HYPOTHESIS ................................................................................................................32 Development of hypothesis ........................................................................................31 Hypothesis ..................................................................................................................32 CHAPTER I ..................................................................................................................33 Abstract .....................................................................................................................34 Introduction .............................................................................................................35 Materials and Methods ............................................................................................37 Purification
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