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Investigation into the structure and function of Hsp47 Umbreen Ahmed A thesis submitted to the University of Birmingham for the degree of Doctor of Philosophy School of Biosciences University of Birmingham Birmingham B15 2TT May 2009 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Acknowledgements Firstly, a huge thanks to my supervisor, Dr Timothy Dafforn for his continuous support, enthusiasm and patience throughout my PhD. It has been a pleasure working for him, even when the lab work has not been particularly rewarding! Our many conversations on cars and formula 1 have been especially enjoyable and will be missed. I would also like to thank our collaborators from Imperial College (Andrew Miller, Dee Olerenshaw, Takayuki Homma, Micheal Wright and Firdaus Abdul) who provided me with the Mus musculus Hsp47 clones. Their mutagenesis work has made this thesis possible and our fruitful discussions have been both interesting and helpful. Thanks also to the James Whisstock group at Monash University, Australia, for providing me with the opportunity to work with such enthusiastic and dedicated scientists. I am indebted to others for their valuable time, expertise and use of instrumentation with regard to specific techniques; Dr Corrine Smith for electron microscopy and Dr Klaus Fütterer for protein crystallography. There are also those who have assisted me in the laboratory – Rosemary Parslow for help with a bit of everything; Anshuman Shukla and Philip Robinson for work on Xenopus laevis and Danio rerio Hsp47; and two project students, Nguyen Le and Emma Pritchard for assistance in the purification of Xenopus laevis and Mus musculus Hsp47, respectively. Many thanks also go to past and present members of 7th floor laboratories; Matt, Denise, Karthik, David, Milly, Michelle, Yukie, Yu Pin, Rich and Raul for providing a friendly working atmosphere. A special thank you to Rachel Kendrick for listening, understanding and helping. Our fabulous trips away have made the last three years unforgettable and hopefully there are many more to come. i I also wish to thank Jyoti Patel, a great friend, whose support, humour and advice has made this experience particularly pleasant. Our countless conversations, scientific or otherwise, have provided me with the motivation to fulfil my true potential. Her friendship is truly appreciated. I am forever indebted to my parents for their unconditional love, understanding and patience throughout. Without their continuous support this thesis would never have happened. Also I am extremely grateful to my brothers, Imran and Farhan, for their constant encouragement, belief and humour. The financial support from Medical Research Council is greatly appreciated. ii Abstract Collagen is the most abundant protein in mammals and is the main protein of connective tissue in animals [1]. It is a fibrous structural protein that is the major component of the extracellular matrix, which provides great tensile strength to ligaments, tendons, bone and skin, for example. Hsp47 is a procollagen and collagen specific chaperone that is thought to be involved in the correct assembly and transport of collagen chains. It is a non-inhibitory member of the serine protease inhibitor superfamily and uses a pH-dependent mechanism for binding and release to/from its substrate. In order to study the function of Hsp47 sufficient quantities of the protein need to be expressed and purified. Previous work on Hsp47 studied mammalian forms of the protein which expressed poorly in bacterial expression systems. This research studied Hsp47 in the poikilothermic vertebrate; Xenopus laevis, the ectothermic vertebrate; Danio rerio and the endothermic vertebrate; Mus musculus in a range of expression systems in order to overcome the low protein expression levels. Mus musculus Hsp47 proved the most successful as it yielded soluble protein that could be used for structural and functional characterisation. A reduction in the pH of the environment triggers a conformational change that is vital for the function of Hsp47. Understanding this structural change is important in understanding the function of Hsp47. Histidine residues are thought to play a vital role in the conformational transition of Hsp47. Histidine variants were made to identify possible binding sites and/or areas involved in the instigation of the structural change in Hsp47. The mutations allowed the first identification of a more stable, latent, serpin state of the protein. Interestingly, this latent form comprised of enhanced biological activity as it reduced collagen fibril formation. One of the mutants lacked any collagen binding ability, which may be an indication of a possible collagen binding site on Hsp47. iii The results presented in this thesis provide an insight into the function and structure of the non-inhibitory serpin Hsp47 and may enhance the understanding of the molecular mechanism by which the collagen-specific chaperone operates. iv Abbreviations Abbreviations used in this thesis were as recommended by the Journal of Biological Chemistry. α1-AT α1-anti trypsin ACT Antichymotrypsin AMP Ampicillin ANGT Angiotensinogen ANS Anilino-8-naphthalene sulphonate AUC Analytical ultracentrifugation BSA Bovine serum albumin CBD Chitin binding domain CBG Cortisol binding globulin CD Circular dichroism DTT Dithiothreitol EK Enterokinase ER Endoplasmic reticulum FRET Fluorescent resonance energy transfer hPCI human protein C inhibitor HSE Heat shock element HSF1 Heat shock factor 1 Hsp Heat shock protein I Intermediate state IPTG Isopropyl-beta-D-thiogalactopyranoside kDa Kilodalton LB Liquid broth v N Native state Ni-NTA Nickel-nitrilotriacetic acid P4-H Prolyl-4-hydroxylase PAI-1 Plasminogen activator inhibitor-1 PDI Protein disulphide isomerase PEG Polyethylene glycol PI Proteinase inhibitor RCL Reactive centre loop RPM Rotations per minute SERPIN Serine protease inhibitor SDS-PAGE Sodium dodecyl sulphate polyacrylamide gel electrophoresis TBG Thyroxine binding-globulin TNF Tumour necrosis factor U Unfolded state UTMP Uterine milk protein WT Wild type 6xHis Hexa-Histidine vi Table of Contents CHAPTER 1: Introduction ..................................................................... 1 1.1 Protein Folding .................................................................................................... 1 1.2 Protein misfolding and aggregation..................................................................... 5 1.3 Macromolecular crowding................................................................................... 7 1.4 Molecular Chaperones in Protein Folding........................................................... 8 1.5 Hsp47................................................................................................................. 15 1.6 Collagen biosynthesis........................................................................................ 17 1.7 Hsp47 and collagen ........................................................................................... 21 1.8 The pH dependant conformational switch mechanism...................................... 29 1.9 Hsp47 as a member of the Serine Protease Inhibitor Superfamily.................... 31 1.9.1 Introduction ................................................................................................ 31 1.9.2 Identification of the Serpin Superfamily .................................................... 31 1.9.3 Serpin Folding ............................................................................................ 34 1.9.4 Serpin Structure .......................................................................................... 37 1.9.4.1 The Breach Region .............................................................................. 39 1.9.4.2 The Shutter Region.............................................................................. 40 1.9.4.3 The Hinge Domains............................................................................. 41 1.9.5 Serpin Function .......................................................................................... 44 1.9.6 Serpin conformations.................................................................................. 47 1.9.6.1 The Native Conformation.................................................................... 49 1.9.6.2 The Cleaved Conformation ................................................................. 49 1.9.6.3 The Latent Conformation .................................................................... 50 1.9.6.4 The Polymers....................................................................................... 51 1.10 The Location of Key Histidines in Hsp47....................................................... 57 1.11 Objectives........................................................................................................ 60 1.12 Aims ................................................................................................................ 61 CHAPTER 2: Materials and Methods................................................
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