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STRUCTURAL ENDEAVORS in the RETINOID (VISUAL) CYCLE By STRUCTURAL ENDEAVORS IN THE RETINOID (VISUAL) CYCLE by LUKAS HOFMANN Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Pharmacology CASE WESTERN RESERVE UNIVERSITY August, 2017 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Lukas Hofmann candidate for the degree of Doctor of Philosophy*. Committee Chair Jason Mears, Ph.D. Committee Member Krzysztof Palczewski, Ph.D. Committee Member Marvin Nieman, Ph.D. Committee Member Focco van den Akker, Ph.D. Committee Member Marcin Golczak, Ph.D. Date of Defense 05.19.2017 *We also certify that written approval has been obtained for any proprietary material contained therein. i Table of Contents List of Tables ........................................................................................................vi List of Figures ...................................................................................................... vii Acknowledgements ..............................................................................................ix Abbreviations ........................................................................................................xi Abstract ................................................................................................................ 1 Chapter 1: Advances in understanding the molecular basis of the first steps in color vision ........................................................................ 3 1.1. Introduction ........................................................................................ 4 1.2. Terminology and phylogeny of human cone visual pigments ............. 5 1.2.1. Background ........................................................................................ 5 1.2.2. Unique photoreceptor physiology improves color perception ............. 6 1.2.3. Properties of trichromacy ................................................................... 7 1.3. Interplay of photoreceptors and neurons in color vison .................... 11 1.3.1. Multichromacy and its dimensions ................................................... 12 1.3.2. Neuronal contribution to color perception ........................................ 15 1.4. Energetics of cis−trans isomerization of 11−cis−retinal ................... 17 1.4.1. Molecular insights into spectral tuning ............................................. 19 1.4.2. Physicochemical limits of human visible spectra ............................. 21 1.4.3. The interplay of light and heat on the activation energy ................... 25 1.4.4. Human vision beyond the visible spectra ......................................... 27 1.4.5. Phototransduction noise of photoreceptor cells ............................... 29 ii 1.5. Molecular insights into color tuning .................................................. 33 1.5.1. Molecular insights into SWS1 color tuning ....................................... 33 1.5.2. Molecular insights into color tuning of M/LWS and L/LWS cones .... 37 1.6. Deficiencies in color vision ............................................................... 41 1.6.1. Tritanopia ......................................................................................... 44 1.6.2. Red−green color deficiency ............................................................. 47 1.6.3. L/LWS−M/LWS genetics .................................................................. 49 1.6.4. Transcription regulation of L/LWS and M/LWS opsin genes ............ 52 1.7. Color vision among species ............................................................. 53 1.7.1. Variations of cone photoreceptor organization throughout species . 58 1.7.2. SWS cones: a distinct member of the retina .................................... 60 1.8. Conclusions ..................................................................................... 66 1.9. Future directions .............................................................................. 68 Chapter 2: An effective thiol-reactive probe for differential scanning fluorimetry with a standard real-time polymerase chain reaction device ............................................................................... 70 2. Assessing the thermal stability of visual GPCRs ................................. 71 2.1. Abstract ............................................................................................ 71 2.2. Introduction ...................................................................................... 73 2.3. Results ............................................................................................. 76 2.4. Discussion ....................................................................................... 81 iii Chapter 3: Structural Insights into the Drosophila melanogaster Retinol Dehydrogenase, a Member of the Short-Chain Dehydrogenase/Reductase Family .............................................. 83 3. Structure of the Drosophila melanogaster retinol dehydrogenase .... 84 3.1. Abstract ............................................................................................ 84 3.2. Introduction ...................................................................................... 85 3.3. Results ............................................................................................. 88 3.4. Discussion ..................................................................................... 102 Chapter 4: Hydrogen/Deuterium Exchange Mass Spectrometry of Human Green Opsin Reveals a Conserved Pro-Pro Motif in Extracellular Loop 2 of Monostable Visual G Protein-Coupled Receptors ..................................................................................... 107 4. Hydrogen/Deuterium Exchange of the Green Cone Pigment, a Member of the Class A GPCRs ............................................................ 108 4.1. Abstract .......................................................................................... 108 4.2. Introduction .................................................................................... 110 4.3. Results ........................................................................................... 115 4.4. Discussion ..................................................................................... 127 Chapter 5: Conclusions and Future directions ............................................ 132 5. Summary ................................................................................................ 133 5.1. Assessing thermal stability of membrane proteins with a PCR device ............................................................................................ 133 iv 5.2. Conformational changes in green cone pigment upon light activation ........................................................................................ 133 5.3. The PDH crystal structure provides mechanistic insight into the initial reaction of the retinoid cycle ................................................. 135 5.4. Conclusion ..................................................................................... 136 6. Appendix ................................................................................................ 138 6.1. An effective thiol-reactive probe for differential scanning fluorimetry with a standard RT-PCR device; Materials and Methods ......................................................................................... 138 6.2. Structural insights into the Drosophila melanogaster retinol dehydrogenase, a member of the short-chain dehydrogenase/reductase family; Materials and Methods ............. 140 6.3. Hydrogen/Deuterium Exchange Mass Spectrometry of Human Green Opsin Reveals a Conserved Pro-Pro Motif in Extracellular Loop 2 of Monostable Visual G-protein Coupled Receptors; Materials and Methods ................................................................... 160 References ....................................................................................................... 178 v List of Tables Table 1: .............................................................................................................. 14 Table 2: .............................................................................................................. 15 Table 3: .............................................................................................................. 43 Table 4: .............................................................................................................. 57 Table 5: .............................................................................................................. 75 Table 6: ............................................................................................................ 142 Table 7: ............................................................................................................ 145 Table 8: ............................................................................................................ 152 Table 9: ............................................................................................................ 153 Table 10: .......................................................................................................... 155 Table 11: .......................................................................................................... 160 Table 12: .......................................................................................................... 168 vi List of Figures Figure 1: ..............................................................................................................
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