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STRUCTURAL and FUNCTIONAL STUDY of the INTERACTION BETWEEN Ki67 FHA DOMAIN and NIFK

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STRUCTURAL and FUNCTIONAL STUDY of the INTERACTION BETWEEN Ki67 FHA DOMAIN and NIFK STRUCTURAL AND FUNCTIONAL STUDY OF THE INTERACTION BETWEEN Ki67 FHA DOMAIN AND NIFK DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Haiyan Song, M. S. ***** The Ohio State University 2007 Dissertation Committee: Approved by Professor Ming-Daw Tsai, Advisor Professor Dale D. Vandre, Co-advisor _________________________________ Professor Ross E. Dalbey Advisor Ohio State Biochemistry Graduate Program Professor Sissy M. Jhiang ABSTRACT Both structural biology and cell biology approaches have been used to study the interaction between the FHA domain from Ki67 and a nucleolar protein NIFK. Ki67 is a nuclear protein that is over-expressed in proliferating cells (G 1, S, G 2 and M- phase), but is extremely down-regulated in quiescent cells (G 0). It is believed to be involved in the regulation of rRNA gene transcription and cell proliferation. However, little is known about the precise function of the protein, due to its large size and lack of homology to other proteins with known functions. In this dissertation, efforts have been made to understand both the structural basis and the biological function(s) of the interaction between the FHA domain from the N-terminal of Ki67 and the nucleolar protein NIFK. Previous studies showed that Ki67 FHA domain binds to a phosphopeptide consisting of NIFK amino acid residues 226 to 269. Preliminary results from protein kinase assays also showed that NIFK (226-269) can be sequentially phosphorylated by kinases CDK1/cyclin B and GSK3 β at Thr238 and Thr234, respectively, in vitro . In this work, we explored the detailed sequential phosphorylation mechanism of NIFK (226- 269) by CDK1/cyclin B and GSK3 β, and revealed that the three proline residues around Thr234 and Thr238 directly regulate the kinase recognition specificities of Thr234 and Thr 238. We also probed the molecular mechanism controlling the multisite interaction ii between the Ki67 FHA domain and NIFK (226-269)_3p. The results showed that, unlike other characterized FHA domains that recognize a pT-X-X-(D/I/L) motif, the Ki67 FHA domain-NIFK (226-269)_3p interaction involves more factors. In addition to the local recognition of the phosphate group from phospho-Thr234, the interaction also requires an extended hydrophobic interface in the middle of the NIFK peptide, and the extension of the β-sheet of the FHA domain by the addition of a β-strand formed by NIFK (260-269). To further shed a light on the biological functions of the Ki67 FHA domain-NIFK (226- 269)_3p interaction, a proteomics study was performed to define the NIFK interactomes during both interphase and mitosis. NIFK was shown to interact with B23, an important nucleolar protein involved in ribosome biogenesis, in an RNA and cell cycle-dependent manner. Ki67 may modulate this interaction via its FHA domain in mitosis. In addition to B23, around 159 proteins were identified by mass spectrometry to interact with NIFK. These proteins were primarily ribosomal proteins and proteins involved in pre-ribosomal RNA processing and ribosome assembly. NIFK was also found to be associated with pre- rRNAs. Knockdown of NIFK gene expression caused accumulation of cells at the G1/S transition in cell cycle progression. Together, these findings suggest that NIFK may function coordinately with Ki67 and B23 in ribosome biogenesis and cell proliferation. They also revealed a possible molecular mechanism through which Ki67 regulates and maintains the balance between ribosome biogenesis and cell cycle progression, by regulating the NIFK-B23 interaction in a cell cycle-dependent manner. The mitosis master kinase CDK1/cyclin B may regulate the interaction of Ki67, NIFK and B23 through phosphorylation, which results in the relocation of NIFK to the surface of mitotic chromosomes where Ki67 is also localized. Such interactions likely serve to inhibit iii rDNA transcription during mitosis, and to promote cell cycle progression during interphase. iv Dedicated to my father v ACKNOWLEDGMENTS I wish to thank my advisor, Dr. Ming-Daw Tsai, for his intellectual support, respect of my individual interest, and encouragement, which has made this dissertation possible. His incredible enthusiasm for science and his passion for research create a wonderful atmosphere in our laboratory that benefits all who are involved. His appreciation of individual differences and interests encouraged me into a new research direction which extremely enhanced and extended my personal strength. As my mentor, he provided an amazing balance between direction and self-direction, which has helped make me an independent researcher. I am grateful to my co-advisor, Dr. Dale Vandre, and my advisory committee member, Dr. Sissy M. Jhiang, for the wonderful collaborations that led me in a new direction where my interest resides. Their unselfish help and support helped me through many difficult times and changed my research path. I also thank my collaborator, Eric S.-W. Chen from the Genomics Research Center in the Academia Sinica, Taiwan, for his great efforts in running all the mass spectrometry experiments and following data analysis. I benefited greatly from these collaborations to become a more multi-faceted researcher. I also wish to thank my great group members. It is a pleasure for me to work with a team of people who really care about one another and are willing to support, help, and vi encourage each other. I thank Dr. Hongyuan Li, Dr. Dongyan Qin, and Dr. Minyong Chen for providing a basic training in my first year and for sharing their invaluable research experience. I also thank Dr. Hyun Lee, Dr. Yu Wang and Shengjiang Tu for their stimulating discussion. I also thank my dear friend Zhaoxia Zhang. I really feel lucky to have a friend like her who treats the problems I face as her own. She provided me with resources ranging from scientific opinions to experimental facilities when I changed to a new research direction. I could not have finished so quickly without her thoughtful help. I always know that there is no way for me to have gotten this far without my family’s support and love. At any hard time, my husband, Ronglin’s supportive words and my lovely little son, Tony’s sweet smile always make me strong and brave. Their love is the best motivation which helped me through this project. Words cannot express my appreciation to Ronglin for sacrificing so much of his own career and for taking good care of Tony and I, which made this work possible! This work is dedicated to my dear father who guided me to be a person with integrity, love, and responsibility. As my role model, my father saw this world with his heart, but not his eyes. I made him proud of me in not only becoming a person who takes care of herself, but also in becoming a person who cares about her family, her friends, her community, her country, and the human society. I also dedicate this work to my mother. She is one of the most unselfish and dedicated mothers in the world. Her precious love and warm heart make me gentle, yet still strong-minded enough to be able to handle various difficulties smoothly. vii VITA September 24, 1975 . .Born – Lanzhou, China 1994-1998 . B. S. Biochemistry, Nankai University 1998-2001 . M. S. Biochemistry, Nankai University 2001-present . .Graduate Teaching and Research Associate, The Ohio State University. PUBLICATIONS 1. Haiyan Song , Eric Chen, Hongyuan Li, Sissy M. Jhiang, Dale Vandre, Ming- Daw Tsai, B23 interacts with NIFK in a cell cycle-dependent manner that may be modulated by Ki67 in mitosis via its FHA domain, submitted to Journal of Biological Chemistry; 2. In-Ja L Byeon, Hongyuan Li, Haiyan Song , Angela M Gronenborn & Ming-Daw Tsai, Sequential phosphorylation and multisite interactions characterize specific target recognition by the FHA domain of Ki67, Nature Structural & Molecular Biology 12, 987 - 993 (2005). FIELDS OF STUDY Major Field: Biochemistry Specialization: Protein Chemistry and Cell Biology viii TABLE OF CONTENTS P a g e Abstract . .ii Dedication . .v Acknowledgments . .vi Vita . viii List of Tables . .xiii List of Figures . xiv List of Abreviations . .xvi Chapters: Chapter 1 Introduction . .1 1.1 Protein-protein interactions & phosphoprotein interacting domains . .1 1.1.1 Protein-protein interactions . .1 1.1.2 SH2 domain . 2 1.1.3 PTB domain . 3 1.1.4 WW domain . 3 1.1.5 14-3-3 domain . .4 ix 1.1.6 WD40 repeats . .5 1.1.7 Polo-box domain . 6 1.2 The FHA domain . .7 1.2.1 Structure of FHA domains . .7 1.2.2 Phospho-Thr binding specificity of FHA domains . 9 1.2.3 Biological functions of FHA domains . 12 1.2.3.1 Rad 53 . .12 1.2.3.2 Chk2 . 14 1.3 Ki67 . .17 1.3.1 The Ki67 protein . .17 1.3.2 Ki67 primary structure . 17 1.3.3 Ki67 and cell proliferation . 18 1.3.4 Ki67 FHA domain . .20 1.4 NIFK . .22 1.4.1 NIFK . 22 1.4.2 RNA recognition motif (RRM) . .23 1.4.3 Nucleolus . 25 1.4.4 B23 . 27 Chapter 2 Exploration of the phosphorylation-dependent multisite interaction between the Ki67 FHA domain and NIFK (226-269)_3p . 46 2.1 Abstract . 46 2.2 Introduction . .47 2.3 Materials and methods . 50 x 2.4 Results . .54 2.4.1 Phophorylation mechanism of NIFK (226-269) . 54 2.4.2 CDK1/cyclin B and GSK3 are associated with NIFK pull down complex . 55 2.4.3 The factors on NIFK_44 which contribute to the interaction . .56 2.4.4 The factors on Ki67 FHA domain which contribute to the interaction .58 2.5 Discussion .
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