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The Pennsylvania State University The Pennsylvania State University The Graduate School Eberly College of Science THERMODYNAMIC CHARACTERIZATION OF THE INTERACTION OF THE TRANSCRIPTION FACTOR PDX1 AND ITS REGULATORY PARTNER SPOP A Thesis in Chemistry by Krystal Diaz © 2018 Krystal Diaz Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science December 2018 The thesis of Krystal Diaz was reviewed and approved* by the following: Scott A. Showalter Associate Professor of Chemistry and Biochemistry and Molecular Biology Thesis Advisor Graduate Program Chair Philip C. Bevilacqua Distinguished Professor of Chemistry and Biochemistry and Molecular Biology Amie K. Boal Assistant Professor of Chemistry and Biochemistry and Molecular Biology *Signatures are on file in the Graduate School. ii Abstract The homeodomain transcription factor Pdx1 is essential for pancreatic development, function, and maintenance. Mutations in pdx1 lead to impairments in beta cell function, glucose tolerance, and insulin secretion that result in diabetic phenotypes. Most clinically documented Pdx1 sequence variants map to disordered regions of the protein whose function is not well-characterized. Our group has confirmed that the disordered C-terminus of Pdx1 participates in essential regulatory interactions and that mutations within this region disrupt binding. The current work aims to elucidate mechanistic detail of the interaction of the Pdx1- C terminal domain with the MATH domain of the E3 ubiquitin ligase adaptor SPOP. This is achieved through the thermodynamic and structural characterization of the Pdx1-SPOP complex, which reveals binding affinities and atomistic details describing the binding event. The effects of multivalency have been assessed through calorimetric and spectroscopic binding assays using minimal peptides encompassing individual Pdx1 binding sites. The results herein provide a molecular level understanding of this interaction crucial to glucose homeostasis. iii Table of Contents List of Figures ............................................................................................ vi List of Tables ............................................................................................ vii List of Abbreviations.................................................................................. viii Chapter 1: Introduction ............................................................................... 1 1.1 General Introduction ............................................................................................... 1 Intrinsically Disordered Proteins ............................................................................... 1 Pdx1: Understanding the Role of IDRs in Transcription ........................................... 3 Pdx1 Structure .......................................................................................................... 6 Pdx1 Interacts with Speckle-type POZ protein (SPOP) Leading to Ubiquitination .... 7 Pdx1-C as a Regulatory Region via Multivalent Interaction with SPOP .................... 9 1.2 Technical Introduction .......................................................................................... 15 Isothermal Titration Calorimetry .............................................................................. 16 Equilibrium Fluorescence Titrations ........................................................................ 18 Determination of the Equilibrium Binding Association Constant ............................. 21 1.3 Thesis Overview................................................................................................... 23 Chapter 2: Examining the role of the Pdx1 C-terminal domain in Pdx1 degradation ............................................................................................... 24 2.1 Introduction .......................................................................................................... 24 2.2 Materials and Methods ......................................................................................... 28 Preparation of Pdx1-C ............................................................................................ 28 Preparation of SPOP MATH ................................................................................... 28 Synthetic peptides .................................................................................................. 29 Table 1. Synthetic peptide sequences for titration experiments .............................. 30 Truncated Pdx1-C constructs ................................................................................. 30 Isothermal Titration Calorimetry .............................................................................. 31 iv Intrinsic Tryptophan Fluorescence Quenching ....................................................... 32 Data Analysis for Tryptophan Fluorescence Quenching Experiments .................... 33 2.3 Results and Discussion ........................................................................................ 35 Nuclear Magnetic Resonance Binding Experiments ............................................... 35 Isothermal Titration Calorimetry .............................................................................. 38 Equilibrium Fluorescence Binding Assays .............................................................. 44 Conclusions ............................................................................................................ 51 Chapter 3: Additional Experiments and Future Directions ......................... 53 3.1 Introduction .......................................................................................................... 53 3.2 Additional Experiments and Preliminary Results for Future Directions ................ 54 Nuclear Magnetic Resonance Assignment of SPOP MATH ................................... 54 Differential Scanning Calorimetry ........................................................................... 56 3.3 Future Directions .................................................................................................. 57 Post-translational Modification of Pdx1-C ............................................................... 58 Thermodynamic Characterization of Clinically Documented Pdx1 Variants ........... 59 References ............................................................................................... 60 v List of Figures Figure 1. Basic schematic of pancreatic β-cell and glucose-dependent processes 4 Figure 2. Structure of Pdx1 adapted from the Pdx1 homeodomain crystal structure 6 Figure 3. Domain architecture of Pdx1 and diabetes-associated variants 7 Figure 4. Crystal structure of SPOP MATH domain bound to a PUC peptide 8 Figure 5. ITC thermogram and binding isotherm for titration of Pdx1-C into SPOP 11 15 15 13 Figure 6. N Pdx1-SPOP N, C-CON showing resonance loss at SPOP binding sites 12 Figure 7. Known SPOP substrates and their consensus binding sequences 14 Figure 8. Diagram of a typical ITC instrument 17 Figure 9. Example ITC thermogram and resultant heat curve 18 Figure 10. Cartoon summary of the conclusions informed by preliminary data 25 Figure 11. Proposed models for Pdx1-C:SPOP interaction 27 Figure 12. Colorized SPOP binding surface 36 Figure 13. NMR titrations of Pdx1 S1 and Pdx1 S2 37 Figure 14. Colorized SPOP MATH surfaces for Pdx1 S1 and Pdx1 S2 binding 38 Figure 15. Titration of 500 µM Pdx1-C into dimeric SPOP28-337 40 Figure 16. Titration of PUC into SPOP MATH at 298 K. 41 Figure 17. Titration of Pdx1 S1 into SPOP MATH 43 Figure 18. Representative overlay of emission spectra from titration with PUC peptide 45 Figure 19. Representative spectral overlay of emission spectra from titration with Pdx1 S1 46 Figure 20. Locations of accessible and buried Trp residues on SPOP 49 Figure 22. Binding curves for fluorescence titrations 50 Figure 23. Langmuir isotherms describing each binding event 51 Figure 24. Assigned HSQC for SPOP MATH 28-166 55 vi List of Tables Table 1. Synthetic peptide sequences for titration experiments 30 Table 2. Sample fluorescence titration experimental design spreadsheet 33 vii List of Abbreviations a.a. Amino Acid A600 Absorbance at 600 nm BACK BTB and C-terminal Kelch domain CD Circular Dichroism ΔCp Change in molar heat capacity DNA Deoxyribonucleic acid DTT Dithiothreitol FT-IR Fourier Transform Infrared Spectroscopy GLUT2 Glucose transporter 2 GST Glutathione-S-transferase ΔH Change in molar enthalpy His6 6X Histidine tag HPLC High Performance Liquid Chromatography HSQC Heteronuclear Single Quantum Coherence IDR Intrinsically disordered protein region IDP Intrinsically disordered protein ins Insulin gene IPTG isopropyl β-D-1-thiogalactopyranoside ITC Isothermal titration calorimetry Ka Equilibrium binding association constant Kd Equilibrium binding dissociation constant LB Lysogeny Broth M Macromolecule MALDI Matrix assisted laser desorption ionization MATH Meprin and Traf Homology Domain MODY4 Mature-onset diabetes of the young 4 Mtot Total macromolecule concentration MWCO Molecular Weight Cutoff MX Concentration of macromolecule-ligand complex n Reaction stoichiometry Ni-NTA Ni2+-nitrilotriacetic acid NMR Nuclear Magnetic Resonance p300 Histone acetyltransferase p300 PDAC Pancreatic ductal adenocarcinoma Pdx1 Pancreatic and duodenal homeobox 1 Pdx1 S1 Pdx1 binding site 1 Pdx1 S2 Pdx1 binding site 2 viii Pdx1-C C-terminus of Pdx1 Pdx1-N N-terminus of Pdx1 PRE Paramagnetic Resonance Enhancement PUC Puckered protein Qobs Observed fluorescence quenching RING Really Interesting
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