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Structure and Function of Multimeric BTB Proteins and Cullin3 Substrate Adaptors

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Structure and Function of Multimeric BTB Proteins and Cullin3 Substrate Adaptors Structure and Function of Multimeric BTB Proteins and Cullin3 Substrate Adaptors by Xian Alan Ji A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Biochemistry University of Toronto © Copyright by Xian Alan Ji 2017 ii Structure and Function of Multimeric BTB Proteins and Cullin3 Substrate Adaptors Xian Alan Ji Doctor of Philosophy Department of Biochemistry University of Toronto 2017 Abstract Oligomerization and ubiquitylation are fundamental to the function of many proteins. Protein oligomerization confers numerous advantages including allosteric regulation, increased coding efficiency, and reduced transcriptional and translational error rates. Ubiquitylation is a widespread post-translational modification that targets modified proteins to a variety of fates including degradation by the 26S proteasome. Dysfunctional protein degradation is a common mechanism shared by a diverse range of human diseases. Many members of the BTB domain superfamily have roles centered on protein oligomerization and ubiquitylation. The BTB domain can facilitate self-assembly to form dimers, tetramers, and pentamers. In addition, many BTB proteins provide substrate specificity for the Cullin3 (Cul3) E3 ubiquitin ligase. Dysfunctional BTB/Cullin3 ubiquitinylation complexes are involved in certain forms of prostate cancer, medulloblastoma, hereditary hypertension and other diseases. Thus, understanding the details of BTB protein oligomerization and Cul3 interaction is important towards many aspects of human disease. The research presented in this thesis addresses several areas of BTB/Cul3 biology. The mechanism of dimeric BTB protein to Cul3 association was expanded to include the contributions iii from the BACK domain observed in the crystal structure of KLHL3/Cul3. Several KLHL3 mutations associated with familial hypertension were found to disrupt Cul3 binding. Next, the structure and oligomeric state of several KCTD family BTB proteins were investigated and found to be pentameric instead of tetrameric. The Cul3 binding properties of several KCTD proteins were characterized and found to be heterogeneous in contrast to other BTB protein families. The structural and functional properties of several KCTD proteins were used to propose a mechanism of KCTD/Cul3 association and the determinants for Cul3 binding. Finally, the structure of the KCTD5/Cul3/Gβγ complex was characterized and the binding affinities of Cul3 and Gβγ to KCTD5 were determined. Overall, these results provide insight into the assembly of multimeric BTB/Cul3 ubiquitylation complexes. iv Acknowledgments I would like to thank my supervisor Dr. Gil Privé for the opportunity to conduct my doctoral research in his laboratory. He has been an invaluable source of mentorship, inspiration, and motivation throughout the years. I would also like to thank my committee members Dr. Lynne Howell and Dr. Stephane Angers for their ideas, advice, and guidance. I would like to thank the past and present members of the Privé lab for their help throughout the years. In particular, I want to acknowledge the assistance provided by Dr. Wesley Errington for pioneering much of the Cullin3 research that formed the foundation of my research. I also want to thank Dr. Hamed Ghanei, Mr. Neil Pomroy, members of the Chakrabartty lab, and members of the Biochemistry Graduate Student Union for their help and friendship. In addition, I would like to thank the staff and administration of the Graduate Department of Biochemistry at the University of Toronto. I owe a big thanks to my wife Mrs. Lucy Jing Lin Xie for her support and enthusiasm. Your endless curiosity and determined pursuit of scientific discoveries will always be a source of inspiration for me. I also owe a great deal to my parents for their many years of hard work raising me and helping me to become the person I am today. v Table of Contents Acknowledgments.......................................................................................................................... iv Table of Contents .............................................................................................................................v List of Abbreviations ..................................................................................................................... ix List of Tables ................................................................................................................................. xi List of Figures ............................................................................................................................... xii Chapter 1 ..........................................................................................................................................1 Introduction .................................................................................................................................1 1.1 Preface..................................................................................................................................1 1.2 Protein oligomerization ........................................................................................................1 1.2.1 Oligomerization simplifies the production of large proteins ...................................2 1.2.2 Allosteric regulation of oligomeric proteins ............................................................3 1.2.3 GPCR oligomerization .............................................................................................5 1.2.4 Heterotrimeric G proteins ........................................................................................6 1.3 The BTB protein superfamily ..............................................................................................6 1.3.1 The BTB-Zinc Finger family ...................................................................................9 1.3.2 The BTB-BACK-Kelch family ................................................................................9 1.3.3 The MATH-BTB family ........................................................................................11 1.3.4 The RhoBTB family ..............................................................................................12 1.3.5 Skp1 and Elongin C ...............................................................................................12 1.3.6 The T1-Kv family ..................................................................................................12 1.3.7 The KCTD family ..................................................................................................13 1.3.8 BTB domain interactions .......................................................................................15 1.4 Protein ubiquitylation.........................................................................................................16 vi 1.4.1 The ubiquitylation cascade ....................................................................................16 1.4.2 The Cullin-RING ligase family .............................................................................19 1.4.3 Regulation of CRL complexes ...............................................................................22 1.4.4 The ubiquitin code .................................................................................................23 1.5 Rationale ............................................................................................................................27 1.6 Thesis overview .................................................................................................................28 Chapter 2 ........................................................................................................................................32 Crystal Structure of KLHL3 in Complex with Cullin3 .............................................................32 2.1 Abstract ..............................................................................................................................32 2.2 Introduction ........................................................................................................................33 2.3 Materials and Methods .......................................................................................................34 2.3.1 Cloning, protein expression and purification .........................................................34 2.3.2 Crystallization, data collection, structure solution and refinement........................35 2.3.3 Size exclusion chromatography .............................................................................37 2.3.4 Isothermal titration calorimetry .............................................................................37 2.3.5 Homology modeling ..............................................................................................38 2.4 Results and Discussion ......................................................................................................38 2.4.1 Crystal structure of the KLHL3/Cul3 complex .....................................................38 2.4.2 KLHL3/Cul3 interaction interface .........................................................................42 2.4.3 Overall architecture of dimeric CRL3 complexes .................................................46 2.4.4 PHAII mutations and Cul3 binding .......................................................................48 2.4.5 Residue positions in other BTB-BACK-KELCH proteins ....................................50 2.5 Conclusions
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