TRIP12 CATALYZES ESTER BOND FORMATION TO PERFORM NON-CANONICAL UBIQUITYLATION

Abstract

Ubiquitination is a dynamic post-translational modification, required in multiple eukaryotic processes. Minimum three different enzymes are required for ubiquitination to take place: a ubiquitin activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3). In distinction, deubiquitinating enzymes (DUBs) regulate the removal of ubiquitin modifications. Together, ubiquitination cascade and deubiquitination promotes a wide range of ubiquitin modifications and further ubiquitin-like modifications. Such posttranslational modification plays a significant role in the regulation of biological processes including proteasomal degradation, DNA damage response (DDR) and cell signaling. Conventionally, ubiquitin was thought to be attached on lysine residue of its substrate forming iso-peptide bond and recently the concept of non-conventional ubiquitination came into play as other amino acid residue can also get ubiquitylated. This thesis examines the non-canonical ubiquitination in HECT domain of E3 ligase Trip12. In this thesis, firstly it is shown that HECT domain of TRIP could undergo mixed canonical and non-canonical ubiquitination. Studying biochemical properties of bond formation between ubiquitin and HECT domain, it is observed the interaction is mediated through oxy-ester bond. In addition to non-canonical ubiquitination, this project presents the branched ubiquitination of HECT domain of TRIP12. Furthermore, presence of oxy-ester bonds during DNA damage conditions is studied.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences