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Investigation of Membrane Receptors' Oligomers Using Fluorescence Resonance Energy Transfer and Multiphoton Microscopy in Living Cells”, UW-Milwaukee, Dec 2016 2 University of Wisconsin Milwaukee UWM Digital Commons Theses and Dissertations May 2017 Investigation of Membrane Receptors’ Oligomers Using Fluorescence Resonance Energy Transfer and Multiphoton Microscopy in Living Cells Ashish K. Mishra University of Wisconsin-Milwaukee Follow this and additional works at: https://dc.uwm.edu/etd Part of the Biophysics Commons, and the Physics Commons Recommended Citation Mishra, Ashish K., "Investigation of Membrane Receptors’ Oligomers Using Fluorescence Resonance Energy Transfer and Multiphoton Microscopy in Living Cells" (2017). Theses and Dissertations. 1513. https://dc.uwm.edu/etd/1513 This Dissertation is brought to you for free and open access by UWM Digital Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UWM Digital Commons. For more information, please contact [email protected]. INVESTIGATION OF MEMBRANE RECEPTORS’ OLIGOMERS USING FLUORESCENCE RESONANCE ENERGY TRANSFER AND MULTIPHOTON MICROSCOPY IN LIVING CELLS by Ashish K. Mishra A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Physics at The University of Wisconsin-Milwaukee May 2017 ABSTRACT INVESTIGATION OF MEMBRANE RECEPTORS’ OLIGOMERS USING FLUORESCENCE RESONANCE ENERGY TRANSFER AND MULTIPHOTON MICROSCOPY IN LIVING CELLS by Ashish K. Mishra The University of Wisconsin-Milwaukee, 2017 Under the Supervision of Professor Valerica Raicu Investigating quaternary structure (oligomerization) of macromolecules (such as proteins and nucleic acids) in living systems (in vivo) has been a great challenge in biophysics, due to molecular diffusion, fluctuations in several biochemical parameters such as pH, quenching of fluorescence by oxygen (when fluorescence methods are used), etc. We studied oligomerization of membrane receptors in living cells by means of Fluorescence (Förster) Resonance Energy Transfer (FRET) using fluorescent markers and two photon excitation fluorescence micro-spectroscopy. Using suitable FRET models, we determined the stoichiometry and quaternary structure of various macromolecular complexes. The proteins of interest for this work are : (1) sigma-1 receptor and (2) rhodopsin, are described as below. (1) Sigma-1 receptors are molecular chaperone proteins, which also regulate ion channels. S1R seems to be involved in substance abuse, as well as several diseases such as Alzheimer’s. We studied S1R in the presence and absence of its ligands haloperidol (an antagonist) and pentazocine +/- (an agonist), and found that at low concentration they reside as a mixture ii of monomers and dimers, and that they may form higher order oligomers at higher concentrations. (2) Rhodopsin is a prototypical G protein coupled receptor (GPCR) and is directly involved in vision. GPCRs form a large family of receptors that participate in cell signaling by responding to external stimuli such as drugs, thus being a major drug target (more than 40% drugs target GPCRs). Their oligomerization has been largely controversial. Understanding this may help understanding the functional role of GPCRs oligomerization, and may lead to the discovery of more drugs targeting GPCR oligomers. It may also contribute toward finding a cure for Retinitis Pigmentosa, which is caused by a mutation (G188R) in rhodopsin, a disease which causes blindness and has no cure so far. Comparing healthy rhodopsin’s oligomeric structure with that of the mutant, may give cues to find the cure. iii © Copyright by Ashish K. Mishra, 2017 All Rights Reserved iv Dedicated with love, To my wife, daughter and my parents v TABLE OF CONTENTS Chapter 1: Introduction ................................................................................................................... 1 1.1 Protein structure .................................................................................................................... 1 1.1.1 Physical interactions in protein structures ...................................................................... 2 1.1.2 Primary structure ............................................................................................................ 2 1.1.3 Secondary structure ........................................................................................................ 5 1.1.4 Tertiary structure ............................................................................................................ 7 1.1.5 Quaternary structure ....................................................................................................... 9 1.1.6 Protein domains .............................................................................................................. 9 1.1.7 Membrane proteins ....................................................................................................... 10 1.2 G Protein-coupled receptors (GPCRs) ................................................................................ 11 1.2.1 GPCR structure ............................................................................................................. 13 1.2.2 G protein binding and signaling ................................................................................... 14 1.2.3 Allosteric modulation of GPCRs .................................................................................. 15 1.2.4 GPCR dimerization and oligomerization ..................................................................... 15 1.3 Sigma-1 receptor (S1R) ....................................................................................................... 19 vi References ................................................................................................................................. 24 Chapter 2: Förster resonance energy transfer (FRET) theory and the kinetic model of FRET .... 32 2.1 Fluorescence ........................................................................................................................ 32 2.1.1 Jablonski diagram ......................................................................................................... 33 2.1.2 Fluorescence vs phosphoresce ...................................................................................... 34 2.1.3 Rate of de-excitation (Γ) ............................................................................................... 34 2.2 FRET ................................................................................................................................... 34 2.2.1 Spectral overlap ............................................................................................................ 37 2.2.2 Stokes shift ................................................................................................................... 38 2.2.3 Quantum yield (QY) ..................................................................................................... 38 2.2.4 Origin and properties of fluorescent proteins ............................................................... 38 2.3 Förster theory ...................................................................................................................... 39 2.3.2 Relationship between quantum yield (Q) and FRET efficiency (Eapp) ......................... 46 2.3.2 Fluorescence lifetime .................................................................................................... 47 2.4 The kinetic model of FRET ................................................................................................. 47 2.4.1 Theoretical FRET efficiency for a parallelogram tetramer model ............................... 50 References ................................................................................................................................. 54 vii Chapter 3: Technology for FRET imaging ................................................................................... 59 3.1 Review of classical methods ............................................................................................... 59 3.1.1 Fluorescence lifetime imaging microscopy (FLIM) ..................................................... 61 3.1.1.1 Time-correlated single-photon counting (TCSPC) .................................................... 63 3.1.2 Photobleaching methods ............................................................................................... 63 3.1.2.1 Donor-photobleaching FRET .................................................................................... 64 3.1.2.2 Acceptor-photobleaching FRET ................................................................................ 65 3.1.3 Fluorescence-polarization FRET .................................................................................. 65 3.2 Optical micro-spectroscopy (OptiMiS) ............................................................................... 68 3.2.1 OptiMiS set-up ............................................................................................................. 69 3.2.2 Multi-wavelength imaging using optiMiS .................................................................... 71 3.3 Using FRET to determine quaternary structure ............................................................... 73 References ................................................................................................................................. 78 Chapter 4: Testing of the kinetic theory of FRET ........................................................................ 84 4.1. Overview ...........................................................................................................................
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