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(Gefs & Gaps) of the Rho Family Structural and biochemical investigation of the activity, specificity and regulation of regulators (GEFs & GAPs) of the Rho family Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Mamta Jaiswal aus Indien Düsseldorf, November 2012 Aus dem Institut für Biochemie und Molekularbiologie II der Heinrich-Heine-Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: PD. Dr. Reza Ahmadian Koreferent: Prof. Dr. Dieter Willbold Tag der mündlichen Prüfung: 23.01.2013 Eidesstattliche Erklärung Hiermit erkläre ich an Eides statt, dass ich die hier vorgelegte Dissertation eigenständig und ohne unerlaubte Hilfe angefertigt habe. Es wurden keinerlei andere Quellen und Hilfsmittel, außer den angegebenen, benutzt. Zitate aus anderen Arbeiten wurden kenntlich gemacht. Diese Dissertation wurde in der vorgelegten oder einer ähnlichen Form noch bei keiner anderen Institution eingereicht und es wurden bisher keine erfolglosen Promotionsversuche von mir unternommen. Düsseldorf, im November 2012 To my family Table of Contents Table of Contents TABLE OF CONTENTS .................................................................................................. I TABLE OF FIGURES .................................................................................................... III PUBLICATIONS ............................................................................................................ IV 1. INTRODUCTION.......................................................................................................... 1 1.1 Rho family proteins...................................................................................................... 2 1.1.1 Gene organization and evolutionary history ............................................................... 3 1.1.2. Role in cellular processes ........................................................................................... 4 1.1.3. The role of Rho family proteins in human disease development ............................... 5 1.1.4. Structural features of Rho family proteins ................................................................. 6 1.1.4.1. G-domain ............................................................................................................................. 7 1.1.4.2. Hypervaribale region (HVR) ............................................................................................... 8 1.1.5. GTPase cycle: Classical biochemical model for Rho proteins ................................ 10 1.2. Regulation of the Rho family GTPases ................................................................... 12 1.2.1. Control of the molecular switch function ................................................................ 12 1.2.2. Different classes of Regulators (GEFs, GAPs, GDIs) ............................................. 12 1.3. Gunanine nucleotide exchange factors (GEFs) ...................................................... 14 1.3.1 Dbl family GEFs ....................................................................................................... 14 1.3.1.1. Structural and functional characteristic of DH domain ..................................................... 17 1.3.1.2. Tandem PH domain of Dbl proteins .................................................................................. 18 1.3. 2. Mechanism of GEF induced nucleotide exchange .................................................. 20 1.3.3. A plethora of Dbl family proteins ............................................................................ 21 1.3.4. Regulation and GEF proteins function .................................................................... 22 1.3.5. GEFs as therapeutic targets ...................................................................................... 22 1.4. GTPase activating proteins (GAPs) ........................................................................ 24 1.4.1. Rho GAP family proteins ......................................................................................... 24 1.4.1.1. Structural and functional characteristic of RhoGAP domain ............................................ 26 1.4.1.2. The mechanism of GAP domain mediated GTP hydrolysis .............................................. 26 1.4.2. Overabundance and diversity ................................................................................... 27 1.4.3. Specificity of RhoGAP domains .............................................................................. 28 1.4.4. Regulation and GAP proteins functions .................................................................. 29 1.5. DLC family RhoGAPs .............................................................................................. 30 1.5.1. Deleted in liver cancer 1 (DLC1)............................................................................. 30 i Table of Contents 1.5.2. Domain organization of DLC family RhoGAPs ...................................................... 30 1.5.3. RhoGAP activity of DLC family ............................................................................. 31 1.5.4. Biological function of DLC1 and its involvement in cancer ................................... 32 1.5.5. DLC1 regulation ...................................................................................................... 33 2. CHAPTER 1 ................................................................................................................. 35 3. CHAPTER 2 ................................................................................................................. 38 2.1. High nucleotide binding affinity of Rho proteins ....................................................... 39 2.2. RhoD and Rif are unique in nature ............................................................................. 40 2.3. Shifted paradigm of for RhoD and Rif ....................................................................... 40 4. CHAPTER 3 ................................................................................................................. 41 4.1.Structure-based interaction sequence matrix ............................................................... 43 4.2. Attributes of catalytic efficiency of the RhoGEFs ...................................................... 43 4.3. Differential roles of the tandem PH domain ............................................................... 44 5. CHAPTER 4 ................................................................................................................. 45 5.1. Specificity of Dbl family proteins ............................................................................... 46 5.2. Efficiency of Dbl family proteins ............................................................................... 46 5.3. Hotspots identification on protein interfaces .............................................................. 47 5.4. RhoD and Rif may not need GEFs ............................................................................. 47 5.5. Not all Dbl proteins are GEFs ..................................................................................... 48 6. CHAPTER 5 ................................................................................................................. 49 7. CHAPTER 6 ................................................................................................................. 52 8. SUMMARY .................................................................................................................. 55 9. ZUSAMMENFASSUNG ............................................................................................. 57 10. REFERENCES ........................................................................................................... 60 11. ABBREVIATIONS .................................................................................................... 82 12. ACKNOWLEDGMENTS ......................................................................................... 84 13. CURRICULUM VITAE ............................................................................................ 86 14. ENCLOSURES .......................................................................................................... 87 ii Table of figures Table of Figures Figure 1. The phylogenetic tree depicting the relationship between Rho proteins................... 4 Figure 2. Structural features of Rho family ................................................................................. 7 Figure 3. Schematic overview of domain organization and biochemical properties of Rho family proteins .................................................................................................... 9 Figure 4. The GTPase regulatory cycle ...................................................................................... 11 Figure 5. Schematic overview of domain organization of Dbl family proteins ....................... 16 Figure 6. Atypical guanine nucleotide exchange factors for Rho family ................................. 17 Figure 7. Structural features of DH-PH domain ....................................................................... 18 Figure 8. Mechanism of the GEF-catalyzed guanine nucleotide exchange reaction .............. 21 Figure 9. Domain organization of RhoGAPs ............................................................................
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