Functional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics

Abstract

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.

Ubiquitin: Structure and Function

“…The mechanism of the 26S proteasomal degradation of unwanted proteins involves covalent binding of a polyubiquitin chain of about four or more ubiquitin moieties to the target proteins to be degraded by formation of isopeptide bonds between the free carboxylate group of ubiquitin's C-terminal Gly 76 and an ε-amino group of the substrates' Lysyl side chains in a process known as ubiquitylation. Protein ubiquitylation is a post-translational modification (PTM) event carried out in a three-step enzymatic process by an E1 ubiquitinactivating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase [13,28,45]. Post-translational modifications (PTMs), which are usually covalent and reversible, may alter the properties and therefore, the functions of the modified protein.…”

“…This notwithstanding, the molecular mechanisms governing ubiquitin recognition in most cases have remained elusive [11,12]. Dysfunction of ubiquitin signalling has been implicated in a wide range of diseases, including cancer, immune disorders, neurodegeneration, cardiovascular and metabolic disorders [13][14][15]. More recently, the demonstration that ubiquitin itself can be modified through phosphorylation by PINK1 provided a major breakthrough linking two very important signalling pathways in cells; phosphorylation and ubiquitylation [16][17][18].…”