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Evolvability of Proteomes: Predicting Protein Function In Evolvability of proteomes: Predicting protein function in the light of evolution Inaugural-Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin by David Fournier from Oullins, France 2014 1 Time period: October 2009 - March 2014 Supervisor: Dr. Miguel Andrade Institute: Max Delbrück Center für Molekulare Medizin, Berlin Buch 1st Reviewer: Prof. Dr. Udo Heinemann, Freie Universität 2nd Reviewer: Prof. Dr. Erich Wanker Date of defense: 04/04/2014 2 Acknowledgements First of all, I would like to thank Miguel Andrade for supervising my work, this has been a great time all along these years thinking about these evolutionary scenarios. Thank you not only for the scientific direction but also the great management. Thank you to all the CBDMers, with whom I had very good connections and lots of fun talking with. I have a special thought for all my colleagues who participated to the Marathon Staffel and other running events in Berlin all these years. That was really a lot of fun to be part of this. Moreover, I salute all my colleagues and friends who joined the weekly experimental lab procedure of wine tasting. I would like to thank Alexandre Budria and Yves Clément for helpful comments and suggestions to the thesis. I thank all collaborators who have participated to the articles I was involved in. I thank especially Prof. Dr. Erich Wanker for providing very interesting data and also for stimulating discussions. Thanks to Alexandre, Prof. Dr. Detlev Ganten and Russ Hodge for their great motivation to organize the seminar on evolutionary medicine. Hopefully there will be more of these conferences in the future and evolution will become part of the medical curriculum as a tool to study diseases and body dysfunctions. I would like finally to thank all my friends and my family, my mother and my sister who were always very supportive. I dedicate this work to the memory of my father. 3 Contents 1. Introduction ............................................................................................................................................... 8 1.1. The place of evolutionary theory in modern biology ............................................................................. 8 1.1.1. First observation: nothing in experimental biology makes sense, except in the light of evolution .... 8 1.1.2. Second observation: new solutions to biological problems using concepts from evolutionary biology are emerging .................................................................................................................................... 9 1.2. Brief reminder of major concepts of evolutionary biology .................................................................. 10 1.3. Evolvability and robustness of living systems ..................................................................................... 12 1.3.1. At the level of genomes .................................................................................................................... 12 1.3.2. At higher degrees of cellular complexity .......................................................................................... 13 1.4. Strategies that promote evolvability .................................................................................................... 14 1.4.1. First strategy: Innovation by gene duplication .................................................................................. 14 1.4.1.1. Concept of gene duplication .......................................................................................................... 14 1.4.1.2. Emergence of protein repeats ......................................................................................................... 14 1.4.2. Second strategy: Evolving new physiological compartments ........................................................... 16 1.4.2.1. Compartmentalization in metazoans .............................................................................................. 16 1.4.2.2. Evolution of physiological systems ............................................................................................... 17 1.5. Methods to study protein mutations using structural and evolutionary information ........................... 18 1.5.1. Mutations in the context of genetic diseases ..................................................................................... 18 1.5.2. Tools to explore the effect of mutations on protein structure and function ...................................... 19 1.5.2.1. Sequence alignment ....................................................................................................................... 19 1.5.2.2. Prediction tools .............................................................................................................................. 19 1.5.2.3. Protein visualization ....................................................................................................................... 19 1.6. Thesis outline ....................................................................................................................................... 20 2. Emergence of proteins with alpha-solenoids .......................................................................................... 21 2.1. Introduction .......................................................................................................................................... 21 2.1.1. Functional and genomic analyses of alpha-solenoid proteins ........................................................... 21 2.1.2. Function of huntingtin alpha-solenoid region and prediction of consequence of mutations for its structure ...................................................................................................................................................... 23 2.2. Detection of alpha-solenoids ................................................................................................................ 23 2.2.1. Introduction to artificial neural networks .......................................................................................... 24 2.2.2. Presentation of the neural network of ARD ...................................................................................... 28 2.2.3. Improvements of ARD ...................................................................................................................... 29 2.2.4. Evaluation of ARD2 performance ..................................................................................................... 31 2.3. Structure of alpha-solenoids................................................................................................................. 34 2.3.1. Some types of alpha-helical repeats are newly classified as alpha-solenoids ................................... 34 2.3.2. Alpha-solenoids can interact with nucleic acids and lipids ............................................................... 35 2.3.3. Alpha-solenoids can be located outside as well as inside of proteins ............................................... 37 2.4. Functions of alpha-solenoids ............................................................................................................... 37 2.4.1. Alpha-solenoid proteins are promiscuous ......................................................................................... 38 2.4.2. Alpha-solenoid proteins are primarily involved in intracellular trafficking...................................... 39 2.4.3. Some proteins are newly detected as containing alpha-solenoids..................................................... 41 2.5. Distribution of alpha-solenoid proteins across the tree of life ............................................................. 43 2.6. Modeling of an alpha-solenoid region of protein huntingtin ............................................................... 47 2.6.1. Introduction ....................................................................................................................................... 47 2.6.2. Methods............................................................................................................................................. 49 2.6.3. Results and discussion ...................................................................................................................... 51 2.6.4. Conclusion ........................................................................................................................................ 59 2.7. General conclusion of chapter 2 ........................................................................................................... 60 4 3. Emergence and evolution of the renin-angiotensin-aldosterone system ................................................. 63 3.1. Introduction .......................................................................................................................................... 63 3.1.1. Introduction to regulation of blood pressure ..................................................................................... 64 3.1.1.1. Definition of blood pressure .......................................................................................................... 64 3.1.1.2. Sensors of blood pressure variation ............................................................................................... 65 3.1.1.3. Effectors of blood pressure ...........................................................................................................
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