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HIV Protein Sequence Signatures for Crosstalk with Host Proteins Mahdi Sarmady Aydin Tozeren, Phd

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HIV Protein Sequence Signatures for Crosstalk with Host Proteins Mahdi Sarmady Aydin Tozeren, Phd HIV protein sequence signatures for crosstalk with host proteins A Thesis Submitted to the Faculty of Drexel University by Mahdi Sarmady in partial fulfillment of the requirements for the degree of Doctor of Philosophy September 2010 © Copyright 2010 Mahdi Sarmady All Rights Reserved. ii Dedications To my parents and in loving memory of my grandfather iii Acknowledgements As with all things in my life, I would first like to thank my family, specially my parents, Mohammad Hossein and Parvin, for giving me solid roots from which I can grow, for showing me the value of education, and for their unconditional support and encouragement by which I could freely pursue my studies. I would like to deeply thank my advisor, Prof. Aydin Tozeren, for his guidance, patience, help, and support during the years of my doctoral studies. I have been very privileged and proud to have him as my advisor. Without his support, this thesis would have not been possible. He has always been there tirelessly for me at every step of the way and his moral and academic supports were always inspiring in times of distress. I extend my sincere gratitude to Prof. Kambiz Pourrezaei who has been always supportive and encouraging from my first day at Drexel. I would like to thank the rest of my thesis committee: Prof. Heinrich Roder, Prof. Afshin Daryoush, Dr. Andres Kriete, and Dr. Ahmet Sacan for their insightful comments. I am grateful to current and past members of the Center for Integrated Bioinformatics at Drexel University: Noor Dawany, Will Dampier, Perry Evans, Yi Chuan Liu, and my other friends for their help and making my doctoral studies enjoyable. iv Table of Contents List of Tables ................................................................................................................................. vi List of Figures ............................................................................................................................. vii Abstract ...................................................................................................................................... viii Chapter 1: Introduction and background .................................................................................. 1 1.1. Summary ............................................................................................................................. 1 1.2. Protein - Protein Interaction Mechanisms ...................................................................... 3 1.3. Linear motifs ....................................................................................................................... 4 1.4. De novo Motif Discovery ................................................................................................... 6 1.5. HIV - Human Protein Interactions .................................................................................. 8 1.6. Significance of the Study ................................................................................................... 9 1.7. Thesis Organization ......................................................................................................... 11 Chapter 2: HIV-1 sequence hotspots for crosstalk with host hub proteins ........................ 13 2.1. Background ....................................................................................................................... 13 2.2. Methods ............................................................................................................................. 16 2.2.1. Data Acquisition ........................................................................................................ 16 2.2.2. Dataset preparation and motif discovery .............................................................. 17 2.2.3. Statistical enrichment ............................................................................................... 18 2.2.4. Hotspots annotation with literature on directed mutagenesis ........................... 19 2.3. Results ................................................................................................................................ 20 2.3.1. HIV sequence hotspots for interaction with host hubs ....................................... 21 2.3.2. Biological context for sequence hotspots ............................................................... 27 2.4. Discussion ......................................................................................................................... 31 2.5. Conclusions ....................................................................................................................... 37 Chapter 3: HIV Nef motifs for crosstalk with host proteins ................................................. 38 3.1. Background ....................................................................................................................... 38 3.2. Methods ............................................................................................................................. 42 v 3.2.1. Data Acquisition ........................................................................................................ 42 3.2.2. Dataset preparation .................................................................................................. 43 3.2.3. Statistical enrichment ............................................................................................... 46 3.2.4. HIV Nef sequence hotspots for crosstalk with host proteins ............................. 47 3.3. Results ................................................................................................................................ 48 3.4. Discussion ......................................................................................................................... 58 3.5. Conclusions ....................................................................................................................... 64 Chapter 4: Connectivity Map of Iron-binding Proteins in HIV infection ........................... 66 4.1. Background ....................................................................................................................... 66 4.2. Methods ............................................................................................................................. 68 4.2.1. Identification of iron-associated proteins .............................................................. 68 4.2.2. Pathway visualization .............................................................................................. 69 4.3. Results and Discussion .................................................................................................... 70 4.4. Conclusions ....................................................................................................................... 80 Chapter 5: Conclusions .............................................................................................................. 81 List of References ........................................................................................................................ 84 Appendices .................................................................................................................................. 96 Vita ................................................................................................................................................ 97 vi List of Tables Table 1. Publically available human PPI databases details ..................................................... 4 Table 2. List of host hub proteins targeted by HIV ................................................................ 21 Table 3. Eukaryotic linear motifs (ELMs) present on HIV and enriched among neighbors of hub proteins ............................................................................................................................ 28 Table 4. HIV amino acid mutations found in research literature within the range of motifs annotated in this study .................................................................................................. 30 Table 5. Available literature information on the binding sites of hubs and HIV-1 proteins binding interactions .................................................................................................................... 35 Table 6. Human Proteins Targeted by Nef with interactions involving protein binding 44 Table 7. Motif Clusters on Nef ................................................................................................. 50 Table 8. Co-occring clusters on Nef and outcompterd proteins ........................................... 63 Table 9. Human Iron binding proteins- HIV-1 interactions .................................................. 71 vii List of Figures Figure 1. Motifs for top 3 hub proteins and their position on HIV proteins ...................... 23 Figure 2. Motif hotspot positions on HIV protein sequences ............................................... 25 Figure 3. Heat map for common s among hub proteins considered in the study ............. 26 Figure 4. Hotspots on HIV protein structures ........................................................................ 31 Figure 5. PROSITE domain annotations for top 19 human protein targeted by nef ......... 45 Figure 6. Motifs presence on Nef sequences ........................................................................... 55 Figure 7. Hotspots and their corresponding H1 proteins .................................................... 57 Figure 8. Motif Clusters highlighted
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