Synaptic G Protein-Coupled Receptor BAI1 Regulation of Interacting Partners: Functional Interaction of Brain Angiogenesis Inhibitor 1 (BAI1) with Murine Double Minute 2 (MDM2) & β-Arrestin 2 Open Access

Chu, Jeffrey (Spring 2020)

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The objective of this thesis is to determine the nature of Brain Angiogenesis Inhibitor 1 (BAI1) association with Murine Double Minute 2 (MDM2) and β-Arrestin 2 and how the co-expression of BAI1 with these proteins affects their respective post-translational modifications. BAI1 is an adhesion G protein-coupled receptor (aGPCR) that is predominantly expressed in the central nervous system and found mainly in neurons. Because BAI1 has been implicated in learning and memory and pathologies such as cancer and schizophrenia, it is essential to map out its crucial protein-protein interactions and post-translational modifications. The N-terminus of adhesion GPCRs are known to be cleaved via autoproteolysis. To shed light on how this might affect signaling, we generated 3 forms of the BAI1 receptor (BAI1 FL, ΔNT, and SL) and found that removal of the BAI1 N-terminus resulted in an increase in G protein-dependent signaling via the Rho-A pathway. Furthermore, we have found that MDM2, the E3 ubiquitin ligase that is responsible for the ubiquitination and subsequent degradation of proteins such as p53 and PSD-95, interacts to a greater degree with the truncated (and more active) forms of BAI1. We have also performed studies involving β-Arrestin 2, a protein responsible for the desensitization and internalization of overactive GPCRs and a known binding partner of both MDM2 and BAI1. We have found that MDM2 and β-Arrestin 2 mutually facilitate each other’s interaction with BAI1.  In regard to post-translational modifications, we have discovered that the presence of MDM2 enhances β-Arrestin 2-dependent ubiquitination of BAI1. We have also found that β-Arrestin 2 enhances MDM2 self-ubiquitination, while BAI1 inhibits this process, and that MDM2 co-expression increases ubiquitination of β-Arrestin 2. This thesis further elucidates the interaction of MDM2 with BAI1 and provides evidence that MDM2 and BAI1 form a triple complex with β-Arrestin 2. Ultimately, this thesis maps and characterizes the interactions between these key synaptic proteins, with the goal of enhancing the understanding of the fundamental biology of these proteins and providing insights that may ultimately lead to treatments of a wide range of pathologies. 

Table of Contents

CHAPTER 1. Introduction                                                                                                  1 - 7

CHAPTER 2. Methods                                                                                                         8 - 12

CHAPTER 3. Results                                                                                                          13 - 16

CHAPTER 4. Discussion                                                                                                    17 - 24

FIGURES                                                                                                                               25 - 33

REFERENCES                                                                                                                       34 - 37

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