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STRUCTURAL INSIGHTS INTO RECOGNITION OF ADENOVIRUS BY IMMUNOLOGIC AND SERUM FACTORS by JUSTIN WAYNE FLATT Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Adviser: Dr. Phoebe L. Stewart Department of Pharmacology CASE WESTERN RESERVE UNIVERSITY May, 2014 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of 4 JUSTIN WAYNE FLATT G 4 candidate for the A DOCTOR OF PHILOSOPHY a degree*. (signed) a JASON MEARS A (chair of committee) A PHOEBE STEWART a A ANDREAS ENGEL A A SICHUN YANG D A AMY RUSCHAK A (date) A DECEMBER 13, 2013 A *We also certify that written approval has been obtained for any proprietary material contained therein. ii To Victoria and Samson. iii TABLE OF CONTENTS List of Tables…………………………………………………………………………….xii List of Figures…………………………………………………………………………...xiv List of Abbreviations…………………………………………………………………….xx Acknowledgements……………………………………………………………………..xxv Abstract……………………………………………………………………………………1 Chapter 1 Introduction and background………….…………………………………..3 1.1 Adenoviruses, from pathogens to therapeutics…………………………....3 1.1.1 Adenoviruses as pathogens………………………………………………..3 1.1.2 Adenovirus structure and cell entry……………………………………….5 1.1.3 Adenoviruses as therapeutic agents……………………………………….9 1.2 Adenovirus-host interactions…………………………………………….10 1.2.1 Host immune response to adenovirus……………………………………...11 1.2.2 Recognition of adenovirus by human alpha defensin 5……………….....12 1.2.3 Recognition of adenovirus by serum factors…………………………….15 iv 1.2.4 Recognition of adenovirus capsid-incorporated HIV antigen……….…..18 1.3 A hybrid structural approach to analyzing adenovirus recognition……...20 1.3.1 Preparation of samples for cryo-EM……………………………………..20 1.3.2. Virus imaging and three-dimensional reconstruction…………………....22 1.3.3 Modeling of cryo-EM maps……………………………………………...25 Chapter 2 Recognition of adenovirus by human alpha defensin 5 involves intrinsic disorder……………………………………………………………….….29 2.1 Abstract……………………………………………………………..……29 2.2 Intro……….…………………………………………………………..….30 2.3 Results…………………………………………………………………....33 Cryo-EM structures of HD5 complexed with neutralization-sensitive and – resistant HAdVs……………………………………………………….....33 Modeling of HD5 monomers at the HAdV vertex…………………….....36 The vertex of the defensin-sensitive HAdV accommodates HD5 dimers…………………………………………………………………….39 Intrinsic disorder at the HD5 binding site……………………………..…40 v Stabilization of defensin-sensitive HAdV vertex region by HD5….........42 2.4 Discussion………………………………………………………………..43 2.5 Material and methods…………………………………………………....48 Cryo-EM and image processing…………………………….…………...48 Atomic model building…………………………………………….…....49 Molecular dynamics flexible fitting………………………………….....50 2.6 Acknowledgements……………………………………………….…….51 2.7 Author contributions…………………………………………….……....51 Chapter 3 Virus-misplaced humoral factor activates innate immunity….…………67 3.1 Abstract………………………………………………………….….…...67 3.2 Report………………………………………………………………..…..68 Cryo-EM and MDFF analysis of the protein-protein interface between FX and HAdV5…………………………………………………………..…..69 Validation of the FX-HAdV5 interaction model………………..………..70 FX decorated virus activates an innate immune response………..….…...72 Conclusion…………………………………………………….…..……...74 vi 3.3 Material and methods……………………………………………………75 Animal studies……………………………………………………….......75 Viruses……………………………………………………………….......75 Electron microscopy, image processing and modeling………………….76 Proteome profiler antibody arrays…………………………………….....77 Antibody for confocal microscopy…………………………………........77 Surface plasmon resonance analyses…………………………………….77 Microarray sample processing…………………………………………...78 Microarray data analysis……………………………………………........78 Ingenuity pathway analysis…………………………………………........79 Promoter analysis of differentially expressed genes……………………..80 Gene ontology category analysis……………………....…………….......80 Statistical analysis………………………………………………………..80 3.4 Acknowledgements………………………………………………………81 Chapter 4 FVII dimerization on adenovirus capsid may influence infectivity…….110 vii 4.1 Abstract…………………………………………………………………110 4.2 Introduction……………………………………………………………..111 4.3 Materials and methods………………………………………………….114 Cells and viruses………………………………………………………..114 Cryo-electron microscopy, image processing, and modeling…………..115 AdV infection in vitro…………………………………………………..117 AdV attachment assay…………………………………………….........118 SPR analyses……………………………………………………………118 Statistical analysis………………………………………………………120 Protein structure assessment number……………………………….......120 4.4 Results…………………………………………………………………..120 Cryo-EM structural analysis adenovirus-FVII interaction……………...120 Mutation of the HVR7 TET amino acid motif reduces the affinity of FVII binding to the virus……………………………………………………...121 FVII is inefficient at supporting virus attachment and cell transduction, despite efficient binding to hexon……………………………….……...123 viii FVII binds HAdV5 hexon in an altered orientation compared to that of FX……………………………………………………………………....124 FVII dimerizes via SP domain interactions when bound to HAdV5 hexon…………………………………………………………….……...125 FVII domain dimerization obscure putative receptor interacting residues within the dimer interface……………………………………….……...127 4.5 Discussion…………………………………………………………........128 4.6 Acknowledgements…………………………………………………......132 Chapter 5 Visualization of adenovirus capsid-incorporated HIV antigen….……...147 5.1 Abstract………………………………………………………………....147 5.2 Intro……….……………………………………….………………........148 5.3 Material and methods…………………………………….…………......152 Cryo-EM and image processing………………………….…………......152 Cryo-EM guided molecular dynamic simulations to model the MPER insertions……………………………………………………….…….....154 5.4 Results……………………………………………………….………….155 ix Cryo-EM structure of AdV vector with capsid incorporated MPER peptide……………………………………………………………..….155 Alpha helices are observed within the AdV capsid and for one MPER insertion……………………………………………………………......157 MPER conformation is constrained by the AdV capsid at one insertion site……………………………………………………………………...157 Strong helical interactions between MPER insertions at the 3-mer sites……………………………………………………………………..158 Transient interactions between MPER insertions at the 2-mer sites…...159 Conformational flexibility of MPER next to penton base……………...160 5.5 Discussion……………………………………………………………....160 5.6 Acknowledgements……………………………………………….….....163 5.7 Author contributions………………………………………….………....164 Chapter 6 Summary of discoveries and future directions……………….………....179 6.1 Insights on immune recognition of adenoviruses……………….……....179 6.1.1 Human alpha defensin opposes capsid disassembly…………….……....179 6.1.2 A role for FX in adenovirus innate immunity………………….….…….182 x 6.1.3 Capsid-incorporated HIV antigen adopts multiple conformations…..….185 6.1.4 Conclusion……………………………………………………….……...187 References…………………………………………………………………………........188 xi LIST OF TABLES Table Page 2.1 Intermolecular nonbonded energies for HD5 monomers with adenovirus vertex proteins…………………………………………………………………………………...52 2.2 Intermolecular nonbonded energies for HD5 dimers with adenovirus vertex proteins…………………………………………………………………………………...53 2.3 Intermolecular nonbonded energies for three HD5 dimers with each of the subunits of fiber and penton base at one defensin-sensitive adenovirus vertex……………………...54 S3.1 Distances at the FX-hexon interface before and after molecular dynamics flexible fitting runs with different starting FX orientations………………………………………90 S3.2 Thirty-four genes co-activated in the spleens of WT and Illr1-/- mice after challenge with HAdV5……………………………………………………………………………...92 S3.3 Differential expression of 34 gene set in the spleens of WT and Illr1-/- mice after challenge with HAdV5 and TEA mutant viruses……………………………………......94 4.1 Binding of FVII to adenovirus vectors and summary of SPR fitting parameters for 1:1 kinetic models…………………………………………………………………………..133 4.2 Intermolecular nonbonded energies between FVII molecules and hexons at the icosahedral 2-fold axis of HAdV5 at the end of three 100-ps MDFF simulations……..134 xii S5.1 Optimization of the helical interface at a 3-mer site with molecular dynamics flexible fitting…………………………………………………………………………………....173 S5.2 Distances between hexon insertion sites at 2-mer regions…………………….......174 xiii LIST OF FIGURES Figure Page 1.1 Schematic representation of the structural organization of AdV based on cryo-EM and X-ray crystallography……………………………………………………………......….28 2.1 Cryo-EM structures of HD5 bound to neutralization-sensitive (Ad5.F35) and –resistant (Ad5.PB/GYAR) chimeric HAdVs………………………………………………...…...55 2.2 Modeling and cryo-EM guided molecular dynamics simulations of the interaction between HD5 monomers and vertex proteins of the defensin-sensitive (Ad5.F35) and defensin-resistant (Ad5.PB/GYAR) HAdV chimeras…………………………………...56 2.3 Movement of the RGD-containing loop and HD5 during the molecular dynamics simulations of the defensin-sensitive (Ad5.F35) and defensin-resistant (Ad5.PG/GYAR) HAdV chimeras………………………………………………………………………….57 2.4 Modeling and cryo-EM guided molecular dynamics simulations of the interaction between HD5 dimers and complete vertex regions of the defensin-sensitive (Ad5.F35) and defensin-resistant (Ad5.PB/GYAR) HAdV chimeras…………………………..…….…59 2.5 Structural malleability of the binding pocket within the defensin-sensitive HAdV chimera (Ad5.F35)………………………………………………………………………61 S2.1 Subnanometer resolution of cryo-EM structures of HD5 bound to neutralization-
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