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Modelado Integrativo De La Estructura 3D De Macromoléculas

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Modelado Integrativo De La Estructura 3D De Macromoléculas UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE CIENCIAS BIOLÓGICAS TESIS DOCTORAL Modelado integrativo de la estructura 3D de macromoléculas Integrative modeling of the 3D structure of macromolecules MEMORIA PARA OPTAR AL GRADO DE DOCTOR PRESENTADA POR Ibai Irastorza Azcarate Director Damien P. Devos Madrid 2018 ©Ibai Irastorza Azcarate, 2018 UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE CIENCIAS BIOLÓGICAS TESIS DOCTORAL Modelado integrativo de la estructura 3D de macromoléculas Integrative modeling of the 3D structure of macromolecules MEMORIA PARA OPTAR AL GRADO DE DOCTOR PRESENTADA POR Ibai Irastorza Azcarate Director Damien P. Devos Madrid, 2018 “Urrunago ikustea lortu badut, erraldoien sobaldetara igo naizelako da. “ Isaac Newton Acknowledgements There are many people that should be in this acknowledgements, because, somehow, I feel that all the people that I know and that I have met in these past four years have contributed, even if a little, in helping me become what I am, because this road has not been just about the work that I have done. I will start with Damien. My sincerest gratitude to you, my mentor and friend, who chose me to start this journey into happiness and despair, despite not knowing what the microbiology platypus was. Thanks a lot for letting me work in what I wanted, for teaching me the differences between bacteria and eukarya, for showing me the Belgium beer world and for being in your office when needed. Thanks a lot for helping me become what I am now. Many thanks to my labmates, Carlos and Elena, for being great friends and bearing with my mental disorders. Also to David, classmate and labmate for a short time. Thanks a lot to all the good people I met at work, Rafa, both Martas, Rocio, Laura, Sandra, Jose María, etc… for their friendship and all the exploding kitten games. I am very grateful to Silvia and Juan also, wonderful people that will always have a little place in my heart. Jose Luis deserves special thanks, my part time boss and full time friend, for teaching me so much and giving me the opportunity to be part of great projects. Thanks a lot also to all the people that collaborated with me and especially to Oriol, a great scientist and friend. I need to thank also to all the people in the CABD and the ones that on Tuesdays become professional football players. Thanks also to the RSG-Spain, great group of people and friends that are doing a great job for young scientists. Mi paso por Sevilla ha sido corto pero intenso, y nunca olvidaré lo que he vivido aquí. He conocido gente maravillosa como Curro, que me ha enseñado a ser mejor persona y he hecho muy buenos amigos como Caitlin, Panos y Sole, que han hecho que me sienta en Sevilla, como en casa, que ya es decir, y siempre les recordaré. Quiero agradecer especialmente a Nico, mi compi de trabajo y pareja de yahtzee, pero sobretodo, un gran amigo. Agradecer también a Antonio y Roma, Leo y Toni, Emilio y Lili, Antonio y Jagger, y Pedro, que han contribuido más de lo que creen a que yo haya terminado esta tesis. Les agradezco también a Laura, Joaquín, Joaquinillo y Julián, que son unos amores y les tengo mucho cariño. Estoy muy contento también de haber conocido a David, mi paisano. Una persona maravillosa y un muy buen amigo. Pero a los que de verdad quiero dar las gracias es a Isabel y Nacho. Unas increíbles personas, pero sobre todo amigos. Les debo mucho a ellos. He crecido mucho con ellos, en lo científico y en lo personal y me han enseñado tanto, que estaré toda la vida en deuda. Muchas gracias. Gracias también a Isabel, Boo, y Juan Carlos, que, aunque ya no esté en Sevilla, siempre le consideraré un buen amigo y le tengo mucho aprecio. Mención aparte para Sigeco, mis hermanos, que siempre habéis estado ahí para apoyarme a las duras y a las maduras: Guiselle nuestro dios y creador, con permiso de Iñigod; Leander, Felix y Soto, la escisión alemana, mis futuros hospederos; Fran, Rafa y Juanlu, los biomonguers, que más me comprenden; Sebas, mi siempre compañero de piso; Isra, el hipster; Santy, el catalán; Juanin, ese pequeño gran hombre; Roca, el esclavista eta Marks, nire kuttuna. Os debo tanto, que, de hecho, si no fuera por Sigeco, no estaría trabajando en ciencia. Epiccc! Gracias también al resto de gente que he conocido en Madrid, pero sobre todo a Useros y Miguel, Irene, David y Charli gente preciosa y mejores amigos. Muchas gracias también a toda la familia de Carla, especialmente a Gladys y Eduardo, mi segunda familia, que siempre, siempre, me han ayudado y los quiero mucho. Eta azkenik, gertuen dazenei. Mila esker aita, ama ta Aitor, nire benetako bihotzak ta esker mila nire familixa osuai, edozein lekutara noiela, badakitx beti hor egongo zariela ta, nire onduen, laguntzen. Arrasateko kuadrilia bebai esker pilua. Nahiz ta oporretan bakarrik ikusi, betiko lagunak izen zarie ta hor egon zarie beti. Baster, Hodei, Txak, Arana, Elorza, Ametz, Beixa, Zaba, Martin, Lopez, Txiri, Xabi, Mikel Arana ta falta dienak. Pero a los que más quiero agradecer es a vosotros, mis verdaderos amores, mis peques, mis bonitas, my moon and stars. Os dedico a vosotras esta tesis. Siempre en mi corazón, Argi, Txula y Carla. Os amo. <3 El Director, Don Damien Paul Devos, Doctor en Ciencias Biológicas y Científico Titular del Centro Andaluz de Biología del Desarrollo (CSIC) y el Tutor, Don Abel Sánchez Jiménez, Doctor en Neurociencias y Profesor en el Departamento de Matemática Aplicada en la Facultad de Biología de la Universidad Complutense de Madrid informan que: La memoria titulada “Modelado Integrativo de la Estructura 3D de Macromoléculas / Integrative Modeling of the 3D Structure of Macromolecules” que presenta Ibai Irastorza Azcarate, para optar al Grado de Doctor, reune las condiciones exigidas por la legislación vigente y tiene la originalidad, el rigor y la calidad científica necesaria para ser presentada. Madrid, 2018 Fdo.: Damien Paul Devos Fdo.: Abel Sánchez Jiménez Table of Contents Resumen/Summary ___________________________________________________________ 1 Introduction ________________________________________________________________ 10 1 Macromolecules ________________________________________________________________ 10 2 Proteins _______________________________________________________________________ 12 3 DNA __________________________________________________________________________ 18 Objectives __________________________________________________________________ 43 Results _____________________________________________________________________ 47 The In Vivo Architecture of the Exocyst Provides Structural Basis for Exocytosis _______________ 47 4Cin: a computational pipeline for 3D genome modeling and virtual Hi-C analyses from 4C data _ 81 A single three-dimensional chromatin compartment in amphioxus indicates a stepwise evolution of vertebrate Hox bimodal regulation __________________________________________________ 119 Regulatory landscape fusion in rhabdomyosarcoma through interactions between the PAX3 promoter and FOXO1 regulatory elements ____________________________________________ 147 Discussion _________________________________________________________________ 176 1 Challenges in the elucidation of macromolecule structures _____________________________ 176 2 What did we learn from the exocyst structure? _______________________________________ 177 3 Contribution of 4C-seq data to the chromatin structure problem through 3D models. ________ 179 4 Integrative approaches are necessary to understand the chromatin ______________________ 182 Conclusions ________________________________________________________________ 191 References _________________________________________________________________ 193 Resumen/Summary Resumen/Summary Resumen El estudio de la estructura de las biomoléculas es fundamental para entender la vida desde un punto de vista molecular. Los métodos directos usados para resolver la estructura de complejos macromoleculares, como la cristalografía de rayos X, están llegando a su límite y el futuro se está abriendo paso para resolver dichas estructuras mediante la integración de datos provenientes de distintas técnicas. El objetivo de esta Tesis ha sido desarrollar métodos integrativos para resolver estructuras de complejos macromoleculares. Se han desarrollado dos métodos, uno dirigido a determinar la conformación de complejos multiproteicos y otro para inferir la estructura de la cromatina de distintas regiones del genoma. El primer método se utilizó para resolver la arquitectura del exocyst, un complejo multiproteico compuesto por 8 proteínas de forma alargada, responsable de fusionar vesículas secretoras a la membrana plasmática. El exocyst ha sido difícil de purificar hasta ahora, y, por ello, ha sido difícil resolver su estructura atómica mediante técnicas convencionales como cristalografía de rayos X o resonancia magnética nuclear. El método combina la información estructural de cada subunidad con las distancias entre ellas obtenidas mediante microscopía óptica. Estas distancias, medidas entre distintos fluoróforos fusionados a los extremos amino y carboxilo terminal de cada subunidad, se usan como restricciones espaciales para resolver la estructura. Nuestra herramienta, gracias a algoritmos optimizadores, genera modelos tridimensionales (3D) del exocyst que cumplen las restricciones impuestas. Mediante el análisis de la población de los mejores modelos, se propuso un modelo representativo. La estructura más representativa del exocyst se asemeja a una mano abierta, donde las subunidades sobresalen desde el
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