Proteinveckning är den process där polypeptider veckas till sina nativa struk-turer. Ogynnsamma miljöförhållanden och vissa genetiska anlag inverkar nega-tivt på veckningsprocessen och ökar därför produktionen av giftiga felveckade proteiner. Felveckade proteiner identifieras och avlägsnas från cellen genom en kvalitetskontrollprocess. I denna process spelar molekylära chaperoner ur Hsp70-familjen en nyckelroll genom att direkt identifiera felveckade proteiner och medverka till deras avlägsnande. Hsp70:s funktion bygger på samspel med en mängd kofaktorer som reglerar dess katalytiska ATPasaktivitet. I denna avhandling har jag använt mig av en kombination av metoder från jästgenetik, cellbiologi och biokemi för att experimentellt få en inblick i hur Hsp70:s funkt-ion regleras av kofaktorer som accelererar nukleotidutbyte, s. k. nukleotidutby-tesfaktorer. Studie I visar att nukleotidutbytesfaktorn Fes1 är nödvändig för kvalitetskontroll av proteiner i cytosolen. Våra genetiska studier visar att Fes1:s aktivitet krävs för att felveckade proteiner i komplex med Hsp70 ska spjälkas av ubiquitin-proteasomsystemet. Mer specifikt så främjar Fes1 en fysiskt förbin-delse mellan dessa komplex och ubiquitinyleringsenzymet Ubr1 som i sin tur sänder det felveckade proteinet för spjälkning i proteasomen. De observerade konsekvenserna av att genetisk inaktivera Fes1 är att felveckade proteiner inte spjälkas utan istället upplagras som proteinaggregat samt aktiverar ett uråldrigt genetiskt stressprogram. Sammantaget visar de experimentalla resultaten att Fes1 sänder felveckade proteiner till spjälkning genom att släppa loss dem från Hsp70. Studie II visar ett ovanligt fall av alternativ splitsning av FES1-transkripten som leder till att de två isoformerna Fes1S och Fes1L uttrycks. De båda isoformerna är fullt aktiva nucleotidsutbytesfaktorer men har olika lokali-sering i cellen. Fes1S lokaliserar till cytosolen och krävs för spjälkning av fel-veckade proteiner. Fes1L däremot lokaliserar till cellkärnan och utgör det första exemplet i jästceller på en nuklotidutbytesfaktor i cellkärnan. Upptäckten av isofomer av en nukleotidutbytesfaktor har betydelse för hur vi ser på mekan-ismen bakom kvalitetkontroll av proteiner. Studie III beskriver mekanmekan-ismen som Fes1 använder för att kontrollera Hsp70:s funktion. Fes1 bär på en evolut-ionärt konserverad N-terminal domän som saknar fast struktur, är modulär och krävs för att Fes1 ska fungera i cellen. Domänen bildar ATP-känsliga komplex med Hsp70, vilket tyder på att den binder i samma säte som felveckade protei-ner och därmed påverkar deras interaktion med Hsp70. Studie IV beskriver en ny metod baserad på homolog rekombination i jäst som underlättar byggandet av plasmider för genuttryck i bakterier. Upptäckerna i avhandlingen ger vid handen att Fes1 spelar en nyckelroll i de mekanismer i cellen som utför kvali-tetskontroll av proteiner och sänder felveckade proteiner för spjälkning i prote-asomen. I ett bredare perspektiv ger dessa fynd viktig information som krävs för att utveckla modeller som beskriver hur Hsp70:s funktion regleras av olika kofaktorer för att delta i veckning och spjälkning av proteiner.
8. Acknowledgements
I am grateful to Dr. Claes Andréasson my guru (supervisor), glad to work as your first PhD student. Thankful for giving me a wonderful opportunity to work on this project. Your patience, guidance and freedom to work in this project helped me a lot to achieve many experimental and scientific writing skills.
I would like to thank my co-supervisor Prof. Per Ljungdahl, for discussions and guiding throughout my studies for the improvement.
I will take this opportunity to thank researcher Prof. Roger Karlsson, Prof.
Eva Severinson and Prof. Ann-Kristin Östlund Farrants for creating good research environment around. This always helped me to keep up the good work. I also thank IFSU facility and thank Stina H for helping me to acquire knowledge on microscopy.
Also would like to thank Prof. Martin Ott, and his group members DBB, Stockholm University for your great inputs on my project during the discus-sions in yeast lab meetings.
I would like to thank my collaborators Prof. Jürgen Dohmen, University of Cologne, Cologne, Germany and Asst. Prof. Marc Friedländer, Stockholm University, Stockholm for the collaboration to execute my projects and your contributions are very much valuable. I would like to thank Prof. Lena Mä-ler and Prof. Peter Brzezinski, DBB, Stockholm University, for providing opportunity to carry out experiments in your laboratory. Jobst L for you kindness and helping me with the CD spectra very much in time.
I would like to thank administrative staff for helping me during my entire studies at MBW-WGI, Stockholm University.
Special thanks to my lab mates Jayasankar, Anna and Ganapathi for all your support, we were not just colleagues also good friends. Jayasankar for the contribution to my project and you are a great teammate. Thanks Ga-napathi - ubiquitin expert in our lab, you have always added good inputs on my project. Thank Anna my Swedish tutor and being contributing to my work and for baking cakes for us. Glad to be with you all, it was really great fun working and the moments are cherishable. Thanks for your patience and taking your time on reading my thesis. Thanks to Mats for your scientific inputs on my project. Finally thank Fabian and João for all the conversa-tions together.
Thanks to Kicki Ryman for being so kind to me and helping whenever re-quired. Thanks to past and present members of Per Ljungdahl group for all the fun together and not making me feel lonely during the beginning of my studies. Thanks to Antonio, Andreas, Fitz and Marina for all crazy talks and joy together. Special thanks to Antonio for you kindness and your scientific thoughts and the experience in teaching together. It was pleasure to work with my present colleagues Misa, Yuan, Anna R, Jaclyn and past colleagues Ming, Natalija, Anna V, Steffi, Fathemehm, Sara, Matthias, Deike for all the fun and discussions during corridor meetings. I always enjoyed playing badminton with Jayashankar, Toni, Matthias and Ming. Within a short span of time, it was nice to interact with Sabarina Büttner and group mem-bers and thank you for the help and discussions. Thanks to my F4 north cor-ridor friends for making it more productive environment.
To my friends and family, you should know that your support and encour-agement was worth more than I can express on paper. I am really indebted for all those who have given me their friendship, stood by me in my odd times and provided me lot of support and practical help.
Personally, I would like to thank my family: my uncle Shivalingappa, Aunt Ratnamma, father Chandappa Gowda, mother Yashodamma for supporting me throughout the years, financially, practically and with moral support. I would like to dedicate my thesis to my uncle Mr. Rudregowda S and his wife, my aunt Shakunthala Y P who actually supported me to reach this goal and would not had happened without their support and encouragement.
I am always grateful to Harsha anna - Geetha akka ; Chaitra akka - Arun anna for your support and encouragement. You and your family have always stood along with me in all my accomplishments and have encouraged me.
Special thanks to my sisters family Sunitha – Mallikarjun, Sudha – Somanath for your immense support all the time and glad to get great sisters like you. You both are my real support and have given me unconditional love throughout my life and studies.
Special thanks to my wife Divya for love, affection and huge support have helped me to accomplish this goal. And thanks to Bhavya, my uncle Shival-ingappa and my aunt Ambika for your affection and support.
My extended thanks to Eshwarappa and family; Late Nagendrappa and his family; C Rudrappa and his family and LG family at Basavapatna for your love and affection and each one of your family members have directly or indirectly contributed to achieve this.
My thanks to Harisha and Shruthi for all the fun together and helping me in all kinds. Harisha you were with me in all my ups and downs. Your thoughts and positive energy are exceptional. I am glad to get a great friend like you and you are very much supportive in professional and personal life and I can never forget that. Thanks to Sagar Manoli for introducing me to the world of Stockholm and all the help and support together with Nirmala.
Thanks Samarth for all the fun and enjoyment together and so many years of friendship being together and Sonam is the best match for you in all aspect.
Thanks to our Stockholm friends Harsha-Shreya; Jayanth-Vinutha;
Swaroop-Praghna for all the fun at get togethers and are never forgettable.
My friends Vinay, Srikanth, Vikaram, Sundar, Vineeth, Ganesh and Ma-hesh whom I met in Stockholm had lot of fun. Your warm friendship and was great being with you guys and we have many unforgettable moments.
My short time at Uppsala made good Uppsalites. Chethan my best friend and for being so helpful at difficult times and all the good memories staying together are always exceptional, Shwetha is your perfect life partner. Nikhil and Lakshmi - thank you so much for the fun together and I am really grate-ful for the hospitality. My buddy Raghuveer and Madhu being a kind friends and it was nice being with you both.
Not but not least, I would like to thank my all relatives and friends who di-rectly or indidi-rectly supported me throughout my studies.
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