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Thacker Front Material Compiled UNIVERSITY OF CALIFORNIA, SAN DIEGO Heparan Sulfate 3-O-sulfation: A Rare Modification in Search of a Function A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Bryan Edward Thacker Committee in charge: Professor Jeffrey D. Esko, Chair Professor Richard Gallo Professor Tracy Handel Professor Karl Willert Professor Benjamin Yu 2014 Copyright Bryan Edward Thacker, 2014 All rights reserved. The Dissertation of Bryan Edward Thacker is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2014 iii DEDICATION To my parents, who always challenged me to do my best and sacrificed to give me every opportunity to succeed. To my wonderful wife, who has been loving and supportive through all the missed dinners and nights as a “single” mom. To my little buddies Easton and Jude, who brighten my life and inspire me every day. iv TABLE OF CONTENTS Signature Page ............................................................................................................... iii Dedication ...................................................................................................................... iv Table of Contents ........................................................................................................... v List of Abbreviations ..................................................................................................... ix List of Figures ................................................................................................................. x List of Tables ................................................................................................................. xi Acknowledgements ...................................................................................................... xii Vita .............................................................................................................................. xiv Abstract of the Dissertation ......................................................................................... xvi Chapter 1 Heparan Sulfate 3-O-sulfation: A Rare Modification in Search of a Function ....................................................................................................... 1 1.1 Summary ....................................................................................................... 1 1.2 Introduction .................................................................................................. 1 1.3 Prevalence of 3-O-sulfation .......................................................................... 4 1.4 Sites of modification by Hs3sts .................................................................... 5 1.5 Insights into substrate specificity from structural studies of Hs3sts .......... 13 1.6 Evolutionary origin of the Hs3sts ............................................................... 19 1.7 Expression patterns of the Hs3sts ............................................................... 21 1.8 Biochemical and physiological implications of 3-O-sulfation ................... 23 1.8.1 Antithrombin ............................................................................... 24 1.8.2 Herpes simplex virus glycoprotein D .......................................... 29 v 1.8.3 Fibroblast growth factors (FGFs) ................................................ 30 1.8.4 Cyclophilin B ............................................................................... 32 1.8.5 Stabilin ......................................................................................... 32 1.9 3-O-sulfation in development and disease ................................................ 33 1.9.1 3-O-sulfation in development ...................................................... 33 1.9.2 Diseases related to 3-O-sulfation ................................................. 35 1.10 Conclusions .............................................................................................. 37 1.11 Acknowledgements .................................................................................. 39 1.12 Literature cited .......................................................................................... 40 Chapter 2 Discovery of Novel Ligands that Depend on 3-O-sulfation ........................ 54 2.1 Summary ..................................................................................................... 54 2.2 Introduction ................................................................................................ 54 2.3 Results ........................................................................................................ 57 2.3.1 Creation of affinity matrices ........................................................ 57 2.3.2 Identification of 3-O-sulfate dependent proteins ......................... 63 2.3.3 Validation of neuropilin-1 as a 3-O-sulfate dependent ligand .... 68 2.4 Discussion ................................................................................................... 69 2.5 Experimental methods ................................................................................ 72 2.5.1 Reagents ...................................................................................... 72 2.5.2 Cell line culture ........................................................................... 73 2.5.3 Affinity matrix production .......................................................... 73 2.5.4 Fractionation on affinity matrices ............................................... 76 2.6 Acknowledgements .................................................................................... 77 vi 2.7 Literature cited ............................................................................................ 77 2.8 Supplemental tables .................................................................................... 83 Chapter 3 Enhanced Binding of Neuropilin-1 to 3-O-sulfated Heparan Sulfate Modulates Neuronal Growth Cone Collapse ................................................................ 92 3.1 Summary ..................................................................................................... 92 3.2 Introduction ................................................................................................ 92 3.3 Results ........................................................................................................ 97 3.3.1 Interaction of neuropilin-1 with 3-O-sulfated heparan sulfate .... 97 3.3.2 3-O-sulfate in semaphorin-3a induced growth cone collapse ... 100 3.4 Discussion ................................................................................................. 105 3.5 Methods .................................................................................................... 109 3.5.1 Reagents .................................................................................... 109 3.5.2 Cell lines .................................................................................... 110 3.5.3 Heparin binding plate ELISA .................................................... 110 3.5.4 Flow cytometry .......................................................................... 111 3.5.5 Mouse models ............................................................................ 112 3.5.6 Growth cone collapse assay ....................................................... 112 3.5.7 Quantitative PCR ....................................................................... 113 3.5.8 Statistics ..................................................................................... 114 3.6 Acknowledgements .................................................................................. 114 3.7 Literature cited .......................................................................................... 115 Chapter 4 Conclusions and Future Directions ............................................................ 120 4.1 Summary ................................................................................................... 120 vii 4.2 Protein fractionation on 3-O-sulfated affinity matrices ............................ 120 4.3 Future directions for affinity fractionation ............................................... 122 4.4 3-O-sulfate modulates axonal growth cone collapse ................................ 125 4.5 Future directions for 3-O-sulfate modulating neuropilin-1 function ........ 126 4.6 Concluding remarks .................................................................................. 129 4.7 Acknowledgements .................................................................................. 130 4.8 Literature cited .......................................................................................... 131 viii LIST OF ABBREVIATIONS AT antithrombin BMP bone morphogenic protein CNBr cyanogen bromide DRG dorsal root ganglion FGF fibroblast growth factor FGFR fibroblast growth factor receptor gD herpes simplex virus glycoprotein D HABP2 hyaluronan binding protein 2 Hs3st heparan sulfate 3-O-sulfotransferase hPLAP human placental alkaline phosphatase HSV herpes simplex virus LIF leukemia inhibitory factor NDST N-deacetylase-N-sulfotransferases NRP neuropilin PAP 3′-phosphoadenosine-5′-phosphate PAPS 3′-phosphoadenosine-5′-phosphosulfate RAGE receptor for advanced glycation endproducts Sema3a semaphorin-3a STAT signal transduction and activator of transcription ix LIST OF FIGURES Figure 1-1. Structure of the antithrombin-binding pentasaccharide
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