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Investigating the Molecular Signatures of Β1-Adrenergic Receptor Activation

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Investigating the Molecular Signatures of Β1-Adrenergic Receptor Activation Investigating the molecular signatures of β1-adrenergic receptor activation Andras Sandor Solt Department of Biochemistry Wolfson College University of Cambridge Submitted: 2018 September This dissertation is submitted for the degree of Doctor of Philosophy [BLANK PAGE] Declaration This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration except as declared in the Preface and specified in the text. (Please see additional note under Declaration in Chapter 3.) It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. It does not exceed the prescribed word limit for the relevant Degree Committee. i Summary Name: Mr. Andras Sandor Solt Thesis title: Investigating the molecular signatures of β1-adrenergic receptor activation In this thesis I have investigated the molecular signatures of receptor activation, using the β1- adrenergic receptor (β1AR) as a prototypical class A G-protein coupled receptor (GPCR). I have used a minimally thermostabilised turkey β1AR and expressed it functionally in insect cells using a baculovirus system. The work described here established the labelling, expression, purification and sample preparation of the receptor in LMNG detergent micelles for use in nuclear magnetic resonance (NMR) spectroscopy. GPCRs are highly dynamic molecular systems, and the use of solution NMR is highly suited to the study of fine structural changes that take place within the receptor as a consequence of receptor activation. To this end the receptor was selectively labelled with 13C at the methyl position of methionine residues. The labelling was carried out during insect cell expression, by supplementing methionine deficient media with the labelled amino acid. In this way the methionines throughout the receptor served as reporters. The radio frequency signals emitted by the nuclei of these labelled residues were monitored. NMR experiments were recorded on the receptor in the presence of ligands of various efficacies together with and without G-protein mimetic nanobodies, and changes in the signal were recorded. This allowed for a pattern of molecular signatures to be established, reporting on the effect ligands and G-protein mimetics have on the receptor. This identified two conformational equilibria, between an inactive and a ligand bound-pre-activated state and between a more and a less active ternary state when bound to a G-protein mimetic. Furthermore, it was also observed that ligand binding to the G-protein mimetic saturated basal active state elicits further changes on the receptor cytoplasmic side, demonstrating that ligand efficacy modulates the nature of receptor interaction with G-proteins, which may underpin partial agonism. It was also observed that ligand binding affects the dynamics and rigidity of the receptor, with a full agonist bound receptor exhibiting extensive µs to ms timescale dynamics, compared to a more rigid nanobody bound state. The increased dynamics suggest that full agonist binding primes the receptor for interaction with various downstream signalling partners. Once this coupling takes place, ligand efficacy determines the quality of interaction in this rigidified system. In addition to activation by ligands, certain proteins, such as antibodies can cause receptor agonism in the absence of a small molecule agonist. An example of this takes place in chronic Chagas’ heart disease, where anti-Trypanosoma cruzi antibodies inappropriately cross-react to β1AR, leading to chronic cardiac overstimulation and heart failure. In this thesis, the production of a published monoclonal antibody fragment was explored, in order to generate a tool for the study of this activation mechanism. ii Dedication and Acknowledgements I would like to dedicate this thesis to all those in my life, whether they be teachers or friends, who encouraged me to “go and find out” and to have fun while doing so. I would like to thank Daniel Nietlispach for his supervision, patience and encouragement as well as for the opportunity to work in his group and on this project. He has been excellent at letting me try out ideas and methods, and I have really appreciated this. I would also like to thank the help, assistance and collegial company of all current and past members of the Nietlispach group, specifically Mark Bostock, Yvonne Yu, Duncan Crick, Rowina Westermeier, Niclas Frei, Chih-Ta Henry Chien, Yi Lei Tan, Prashant Kumar and Teyam Peryie. I have enjoyed going to work every day with these people, especially Niclas, Henry, Mark, Yi Lei, Prashant and Teyam. The atmosphere and degree of collaboration that emerged from this company of friends is something truly unique. Aspects of this work would have not been possible without the people at the Novartis Institute for BioMedical Research (NIBR). I am indebted to the help of Binesh Shrestha. I thank him for his hands- on mentoring and the kind assistance of every single member of his group and of others in the lab: Susan Roest, Julia Klopp, Sebastian Rieffel and Agnieszka Sitarska. Throughout this PhD, I have had the unending support of my girlfriend Joanna. I couldn’t have asked for a better partner to go through this journey with. I am also indebted to my parents for their efforts and energy that lead me to being here today. I would like to say special thanks to Alfie for bringing endless amounts of feline joy to my life. This work was made possible by my funders: The MRC and NIBR through the CASE studentship, the Cambridge Philosophical Society and Wolfson College. I am thankful for their sponsorship. iii Table of contents Declaration ............................................................................................................................................... i Summary ................................................................................................................................................. ii Dedication and Acknowledgements ...................................................................................................... iii Table of contents ................................................................................................................................... iv List of Figures ........................................................................................................................................ vii List of Tables .......................................................................................................................................... ix List of abbreviations ................................................................................................................................ x Chapter 1 – Introduction ......................................................................................................................... 1 1.1 – G-protein Coupled Receptors .................................................................................................... 1 1.1.1 – GPCR Classification .................................................................................................................. 1 1.1.2 – GPCR signalling .................................................................................................................... 3 1.2 – The β-adrenergic receptors ........................................................................................................ 8 1.2.1 – β1AR Signalling..................................................................................................................... 8 1.2.2 – Crystallographic studies of the β-adrenergic receptors ...................................................... 9 1.2.3 – Engineering the β1AR for crystallisation ........................................................................... 11 1.2.4 – Insights from β1AR Crystal structures ............................................................................... 12 1.3 – GPCRs are dynamic molecules ................................................................................................. 16 1.3.1 – Receptor plasticity............................................................................................................. 16 1.3.2 – Solution state NMR can provide insights into the dynamic nature of β-adrenergic receptors ....................................................................................................................................... 18 1.4 – GPCR-interacting antibodies .................................................................................................... 21 1.4.1 – Antibodies as tools for structural biology ......................................................................... 22 1.4.2 – Antibodies as therapeutic agents ..................................................................................... 32 1.4.3 – Antibodies as natural modulators of GPCR function ........................................................ 37 1.4.3.1 – Trypanosoma cruzi ribosomal P proteins are major antigens in Chagas’ disease ........
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