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Tyk2 Jh2 Jh1 Jak2 HENRIK HAMMARÉN Intramolecular Regulation of Janus Kinases Acta Universitatis Tamperensis 2338 HENRIK HAMMARÉN Intramolecular Regulation of Janus Kinases AUT 2338 AUT HENRIK HAMMARÉN Intramolecular Regulation of Janus Kinases ACADEMIC DISSERTATION To be presented, with the permission of the Faculty Council of the Faculty of Medicine and Life Sciences of the University of Tampere, for public discussion in the Jarmo Visakorpi auditorium of the Arvo building, Arvo Ylpön katu 34, Tampere, on 15 December 2017, at 12 o’clock. UNIVERSITY OF TAMPERE HENRIK HAMMARÉN Intramolecular Regulation of Janus Kinases Acta Universitatis Tamperensis 2338 Tampere University Press Tampere 2017 ACADEMIC DISSERTATION University of Tampere, Faculty of Medicine and Life Sciences Finland Supervised by Reviewed by Professor Olli Silvennoinen Adjunct professor Michael Courtney University of Tampere University of Turku Finland Finland Adjunct professor Outi Kilpivaara University of Helsinki Finland The originality of this thesis has been checked using the Turnitin OriginalityCheck service in accordance with the quality management system of the University of Tampere. Copyright ©2017 Tampere University Press and the author Cover design by Mikko Reinikka Acta Universitatis Tamperensis 2338 Acta Electronica Universitatis Tamperensis 1843 ISBN 978-952-03-0607-6 (print) ISBN 978-952-03-0608-3 (pdf) ISSN-L 1455-1616 ISSN 1456-954X ISSN 1455-1616 http://tampub.uta.fi Suomen Yliopistopaino Oy – Juvenes Print Tampere 2017 441 729 Painotuote Contents List of Original Communications ...................................................................................... 7 List of Abbreviations ......................................................................................................... 8 Abstract .......................................................................................................................... 11 Tiivistelmä ...................................................................................................................... 13 1 Prelude ................................................................................................................ 14 2 Review of the Literature ...................................................................................... 15 2.1 Protein kinases and cytokine signalling .................................................... 15 2.1.1 The eukaryotic protein kinase family ....................................... 15 2.1.2 Pseudokinases .......................................................................... 20 2.2 Janus kinases and JAK–STAT signalling ..................................................... 21 2.2.1 A brief history of JAK–STAT ...................................................... 21 2.2.2 The JAK–STAT signal transduction pathway ............................. 22 2.3 Regulation of JAK–STAT signalling ............................................................ 27 2.4 JAK mutations and JAK-mediated diseases ............................................... 29 2.4.1 JAK loss-of-function mutations ................................................. 31 2.4.2 JAK gain-of-function mutations ................................................ 32 2.5 Structure and function of JAK domains .................................................... 39 2.5.1 FERM-SH2 ................................................................................. 40 2.5.2 JH2 and JH1 ............................................................................... 42 2.5.3 Mechanism of JAK2 hyperactivation — lessons from inhibitory mutations ................................................................. 45 3 Aims of the Study ................................................................................................ 49 4 Materials and Methods ....................................................................................... 50 4.1 Plasmid constructs, cloning, and site-directed mutagenesis (I–IV) .......... 50 4.1.1 Mammalian expression constructs (I–IV) ................................. 50 4.1.2 Expression constructs for recombinant protein production in insect cells (I, II, IV)............................................. 50 4.1.3 Site-directed mutagenesis (I–IV) .............................................. 51 4.2 Mammalian cell culture, transfection, and cytokine stimulation (II, III, IV) ................................................................................................... 53 4.2.1 Luciferase reporter signalling assays (III, IV) ............................ 53 4.3 SDS-PAGE and immunoblotting (II, III, IV) ................................................ 54 4.4 Recombinant protein production and purification (I, II, IV) ..................... 54 4.5 Analysis of recombinant proteins (I, II, IV) ............................................... 55 4.5.1 Thermal shift assay (TSA) by differential scanning fluorometry (DSF) (I, II, IV) ....................................................... 55 4.5.2 Fluorometric nucleotide-binding assay with MANT-ATP (I, II) .......................................................................................... 55 4.5.3 ADP production assay (I) .......................................................... 56 4.5.4 Surface plasmon resonance measurements (I) ........................ 56 4.5.5 Protein structure determination with X-ray crystallography and small-angle X-ray scattering (I) ................ 57 4.6 In vivo bone marrow transplantation model (II) ...................................... 57 4.7 Molecular dynamics simulations and analysis of trajectories (II, III) ............................................................................................................. 57 5 Summary of the Results ...................................................................................... 59 5.1 Structural and functional characterisation of recombinant JAK JH2s (I, II) .................................................................................................. 59 5.1.1 The crystal structure of TYK2 JH2 (I) ........................................ 59 5.1.2 TYK2 JH2 is an inactive pseudokinase (I) .................................. 59 5.1.3 Characterisation of the nucleotide-binding site of JAK JH2s (I, II) .................................................................................. 60 5.2 Effects of mutational disruption of the JAK JH2 ATP-binding site (I, II) .......................................................................................................... 61 5.3 Hyperactivation of JAKs requires a functional ATP-binding site in JH2 (II)....................................................................................................... 63 5.4 The Inhibitory JH2–JH1 Interaction (III) .................................................... 65 5.4.1 Modelling the interaction using a supercomputer .................. 65 5.4.2 Characterisation and functional validation of the JH2– JH1 inhibitory interaction ......................................................... 65 5.5 Mechanisms of JAK activation and inhibition thereof (II, IV) ................... 68 5.5.1 Systematic analysis of inhibitory mutations ............................ 68 5.5.2 Testing other hypotheses for the function of JH2 (IV) ............. 70 5.5.3 Identification of a JH2 interface critical for heteromeric JAK2 signalling .......................................................................... 72 6 Discussion ........................................................................................................... 73 6.1 JAK structure ............................................................................................ 74 6.2 Structure–function considerations of JH2 ................................................ 75 6.2.1 Protein kinase (in)activity of JH2s ............................................. 75 6.2.2 Nucleotide binding in JH2s ....................................................... 75 6.3 Activation and inhibition of JAKs .............................................................. 76 6.3.1 The JH2–JH1 interaction ........................................................... 76 6.3.2 The JH2-JH1 inhibitory interaction model ................................ 77 6.3.3 JAK activation by mutation (cytokine-independent) ................ 79 6.3.4 Inhibitory mutations and loss of ATP binding to JH2 suppress ligand-independent activation .................................. 82 6.3.5 JAK activation by cytokine ........................................................ 84 6.3.6 The consequences of ATP binding to JAK2 JH2 ........................ 86 6.4 Implications for JAKs as Drug Targets ....................................................... 86 6.4.1 The JH2 ATP-binding site as a drug target ................................ 87 7 Summary and Conclusions .................................................................................. 90 8 Acknowledgements ............................................................................................. 92 9 References ........................................................................................................... 96 10 Original Communications .................................................................................. 124 6 List of Original Communications This thesis is based on the following original communications, which are referred to hereafter by their roman numerals (I-IV). I. MIN, X., UNGUREANU, D., MAXWELL, S., HAMMARÉN, H.M., THIBAULT, S., HILLERT, E., AYRES, M., GREENFIELD, B., EKSTEROWICZ, J., GABEL, C.,
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