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Human Pyroglutamyl Peptidases and Their Involvement in Alzheimers Disease

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Human Pyroglutamyl Peptidases and Their Involvement in Alzheimers Disease HUMAN PYROGLUTAMYL PEPTIDASES AND THEIR INVOLVEMENT IN ALZHEIMERS DISEASE Submitted by Justyna Słonka to the University of Exeter as a thesis for the degree of Doctor of Philosophy in Biosciences (November 2011) This thesis is available for Library use on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. I certify that all material in this thesis which is not my own work has been identified and that no material has previously been submitted and approved for the award of a degree by this or any other University. Signature: …………………………………………………………. 1 Acknowledgments I would like to thank my supervisor, Prof. Jenny Littlechild for her support, guidance and encouragement during this project. I also wish to thank Dr Janet Holley and Prof. Nick Gutowski from Peninsula Medical School for their time, advice and teaching me techniques of AD immunostaining. I should also acknowledge the OPPF-UK team, particularly Dr Ray Owens and Dr Jo Nettleship for their help during a study on PcpII expression. I would like to thank everyone in Biocat for their help and special thanks should be given to Halina, Rita, Nick and Vahid for being the best friends in the world. Lastly, I would like to thank my beloved husband for his constant support and love. 2 Abstract The N-terminally pyroglutamyl-modified β-amyloid (Aβ) peptides are found in abundance in the pathological Alzheimer disease (AD) brain deposits. Such modification not only increases the hydrophobic properties of a given molecule, but also plays a protecting role against proteolytic degradation. This project involved the study of the human type I and type II pyroglutamyl peptidases and their involvement in Aβ processing in AD. Human PcpI has been successfully overexpressed in Escherichia coli strain and purified to homogeneity. The protein displayed significant instability in vitro. To overcome this problem a number of methods were employed such as screening for an optimal protein expression system and buffer composition, site-directed mutagenesis and chemical modification of selected surface residues. This resulted in the selection of the HEPPS buffer system as providing the most stabilising conditions for human PcpI. Improvement in the protein stability enabled initial crystallisation experiments and the identification of favourable conditions for crystal production. Further optimization of this process is needed in order to obtain good quality crystals which are required for structural study. The study on human PcpII involved an extensive screening for optimal expression conditions in bacterial, baculovirus/insect and mammalian systems. The truncated PcpII isoform PcpII/S62-H1024, which lacks the N-terminal transmembrane domain, was successfully expressed and secreted from the HEK 293T cell line using three different pOPIN-based constructs. Moreover, homology modelling of human PcpII catalytic domain was performed, which helped to gain an insight into the three-dimensional structure of the protein and its mode of substrate binding. Lastly, immunohistochemical staining of the human AD brain tissue sections was performed to compare the level and distribution of PcpI and PcpII enzymes between diseased and control cases. The results confirmed that the neurodegenerative conditions lead to the increased synthesis of both enzymes in the cortical AD tissues. Additionally PcpI was shown to be able to participate in the degradation of pGlu-modified Aβ peptides. 3 List of content Acknowledgments ........................................................................................................... 2 Abstract ........................................................................................................................... 3 List of content ................................................................................................................. 4 List of figures ................................................................................................................ 12 List of tables .................................................................................................................. 15 Abbreviations ................................................................................................................ 16 Chapter 1 – Introduction ............................................................................................. 19 1.1. Introduction to Alzheimer’s disease ........................................................................ 19 1.1.1. Disease of 20th century ...................................................................................... 19 1.1.2. Pathology of Alzheimer’s ................................................................................... 20 1.1.2.1. Changes to AD brain ..................................................................................... 20 1.1.2.2. Neurofibrillary tangles (NFTs) ..................................................................... 22 1.1.2.3. Senile plaques and congophilic angiopathy .................................................. 25 1.1.3. β-amyloid peptides (Aβs) ................................................................................... 28 1.1.3.1. APP processing and synthesis of Aβ peptides .............................................. 28 1.1.3.2. Function and neurotoxic effect of Aβ peptides ............................................. 32 1.1.3.3. Modifications of Aβ peptides ....................................................................... 34 1.1.4. Aetiology and treatment strategy of AD ............................................................. 39 1.1.4.1. Factors behind AD pathogenesis .................................................................. 39 1.1.4.2. Potential therapeutic strategies ..................................................................... 41 1.2. Pyroglutamyl peptidases .......................................................................................... 44 1.2.1. General characteristics ........................................................................................ 44 1.2.2. Role of the pyroglutamyl group .......................................................................... 45 1.2.3. Prokaryotic pyroglutamyl peptidases ................................................................. 49 1.2.4. Eukaryotic pyroglutamyl peptidases................................................................... 59 1.2.4.1. Pyroglutamyl peptidase type I ...................................................................... 59 1.2.4.2. Pyroglutamyl peptidase type II and serum thyroliberinase .......................... 63 1.2.4.3. Physiological role of pyroglutamyl peptidase .............................................. 64 1.2.5. Application of pyroglutamyl peptidases ............................................................. 66 1.3. Aims of project ........................................................................................................ 67 4 Chapter 2 – General Materials and Methods ............................................................ 68 2.1. Reagent grade chemicals and equipment................................................................. 68 2.2. Growth media and antibiotics .................................................................................. 68 2.2.1. Luria-Bertani broth (LB) .................................................................................... 68 2.2.2. Selective agar plates ........................................................................................... 68 2.2.3. SOC medium ...................................................................................................... 69 2.2.4. Antibiotics and other basic solutions .................................................................. 69 2.3. Buffers and basic solutions ...................................................................................... 70 2.3.1. Agarose gel electrophoresis ................................................................................ 70 2.3.2. SDS-polyacrylamide gel electrophoresis (SDS-PAGE) ..................................... 70 2.3.3. Protein purification ............................................................................................. 71 2.3.3.1. Tris-HCl buffers (pH 7.5) – 6xHis-PcpI purification ................................... 71 2.3.3.2. K2HPO4/KH2PO4 buffers (pH 8.0) ............................................................... 71 2.3.3.3. Tris-HCl buffers (pH 7.5) – PcpI-6xHis purification ................................... 72 2.3.3.4. Tris-HCl buffers (pH 7.5) – native PcpI purification ................................... 72 2.3.3.5. HEPPS buffers (pH 8.0)................................................................................ 72 2.3.4. Activity assay...................................................................................................... 73 2.3.5. In-Fusion™ cloning ............................................................................................ 73 2.3.6. Phosphate buffered saline (PBS) buffers ............................................................ 73 2.4. Escherichia coli strains ............................................................................................ 74 2.4.1. DNA cloning strains ........................................................................................... 74 2.4.2. Protein expression strains ..................................................................................
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