Structural Studies of Bromodomain and Extra-Terminal Domain Protein BRD3

Abstract

The work presented in this Thesis examines aspects of the molecular mechanisms underlying gene regulation, focusing on the bromodomain and extra-terminal domain (BET) protein family. BET proteins use their tandem bromodomains to bind acetylated lysines, such as those present on histones or transcription factors, while the extra-terminal (ET) domain has been described as a putative protein:protein interaction domain. This Thesis aims to connect these two functions, one in the recognition of post-translational modifications relevant to transcriptional activity and the other the recruitment of transcriptional machinery to specific sites in the genome. What emerges is a model wherein the bromodomains and ET domain work in synchrony to carry out various BET protein functions, both in normal and disease pathways. Additionally, the potential of the BET proteins to associate with themselves, each other, and other potential partners is addressed. Overall, this work provides another component to the emerging story of the complex molecular choreography underlying gene regulation.