Julius Dongdem

By Julius Tieroyaare Dongdem and Cletus Adiyaga Wezena

E3 ubiquitin ligases of which there are >600 putative in humans, constitute a family of highly heterogeneous proteins and protein complexes that are the ultimate enzymes responsible for the recruitment of an ubiquitin loaded E2 ubiquitin-conjugating enzyme, recognise the appropriate protein substrate and directly or indirectly transfer the ubiquitin load onto the substrate. The aftermath of an E3 ligase activity is usually the formation of an isopeptide bond between the free carboxylate group of ubiquitin’s C-terminal Gly76 and an ε-amino group of the substrate’s Lys, even though non-canonical ubiquitylation on non-amine groups of target proteins have been observed. E3 ligases are grouped into four distinct families: HECT, RING-finger/U-box, RBR and PHD-finger. E3 ubiquitin ligases play critical roles in subcellular signalling cascades in eukaryotes. Dysfunctional E3 ubiquitin ligases therefore tend to inflict dramatic effects on human health and may result in the development of various diseases including Parkinson’s, Amyotrophic Lateral Sclerosis, Alzheimer’s, cancer, etc. Being regulators of numerous cellular processes, some E3 ubiquitin ligases have become potential targets for therapy. This chapter will present a comprehensive review of up-to-date findings in E3 ligases, their role in the pathology of disease and therapeutic potential for future drug development.

Part of the book: Hydrolases

By Julius T. Dongdem, Simon P. Dawson and Robert Layfield

Ubiquitin is a small (8.6 kDa) protein that is found ‘ubiquitously’ in eukaryotic organisms and functions as a regulator of numerous cellular processes. It is a multifaceted post-translational modifier of other proteins involved in almost all eukaryotic biology. Once bound to a substrate, ubiquitin initiates a plethora of distinct signals with unique cellular outcomes known as the ‘ubiquitin code’. More recently, much progress has been made in characterising the roles of distinct ubiquitin modifications though it is anticipated that more is yet to be unravelled as several questions remain elusive. The major aim of this chapter is to comprehensively review in detail using published data, the current understanding of the physico-chemical properties and structure (primary, secondary and tertiary) of ubiquitin, outlining current understanding of ubiquitin signal regulatory functions (Ubiquitin Proteasome System) and ubiquitin combinations, with emphasis on the structural relation to its function. Synthesis of ubiquitin (genes) will be illustrated. Additionally, ubiquitin-mediated processes and various possible covalent modifications of ubiquitin and their known functions will be illustrated. Deubiquitinase-dependent deubiquitylation of the ubiquitin code will also be described. Finally, ubiquitin-binding proteins and their ubiquitin-binding domains, the consequences of post-translational modification of ubiquitin by phosphorylation and future prospects will be discussed.

Part of the book: Modifications in Biomacromolecules