Structural Diversity of Ubiquitin E3 Ligase

Abstract

The post-translational modification of proteins regulates many biological processes. Their dysfunction relates to diseases. Ubiquitination is one of the post-translational modifications that target lysine residue and regulate many cellular processes. Three enzymes are required for achieving the ubiquitination reaction: ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). E3s play a pivotal role in selecting substrates. Many structural studies have been conducted to reveal the molecular mechanism of the ubiquitination reaction. Recently, the structure of PCAF_N, a newly categorized E3 ligase, was reported. We present a review of the recent progress toward the structural understanding of E3 ligases.

The NEL Family of Bacterial E3 Ubiquitin Ligases

“…At the C-terminal end, it has two glycine residues, which constitute an essential motif for its activity. At a functional level, the covalent binding of ubiquitin to target proteins during the process known as ubiquitination constitutes one of the most important cell signaling mechanisms to maintain cell homeostasis [ 37 , 38 ].…”

“…E1 activity leads to the formation of a thiol ester link between G76 from ubiquitin and cysteine from the active E1 site [ 50 , 51 ]. Subsequently, the E1-ubiquitin complex interacts with the ubiquitin-conjugating enzyme (E2), which promotes the transfer of ubiquitin from one enzyme to the other due to conformational changes that favor the approach of both active sites [ 37 ]. The final step of the process involves the interaction of the E2-ubiquitin complex with the ubiquitin ligase (E3), which carries out the transfer of ubiquitin to the substrate [ 37 ].…”

“…Subsequently, the E1-ubiquitin complex interacts with the ubiquitin-conjugating enzyme (E2), which promotes the transfer of ubiquitin from one enzyme to the other due to conformational changes that favor the approach of both active sites [ 37 ]. The final step of the process involves the interaction of the E2-ubiquitin complex with the ubiquitin ligase (E3), which carries out the transfer of ubiquitin to the substrate [ 37 ]. The E3s are responsible for selecting the final substrate for the ubiquitination reaction and catalyzing the formation of a peptide bond between the C-terminal G76 of ubiquitin and the amino group of the substrate lysine [ 37 ].…”

“…The final step of the process involves the interaction of the E2-ubiquitin complex with the ubiquitin ligase (E3), which carries out the transfer of ubiquitin to the substrate [ 37 ]. The E3s are responsible for selecting the final substrate for the ubiquitination reaction and catalyzing the formation of a peptide bond between the C-terminal G76 of ubiquitin and the amino group of the substrate lysine [ 37 ].…”

“…Classically, three families of E3 ubiquitin ligases are recognized: Really Interesting New Gene (RING), Homologous to E6AP C-Terminus (HECT), and RING Between RING (RBR). This classification is based on the specific structural characteristics and the ubiquitin transfer mechanism of the enzyme [ 37 ]. The RING E3 ligases promote the transfer of ubiquitin directly from E2 to the substrate, while the HECT and RBR ligases have a conserved cysteine residue where the ubiquitin binds before being transferred to the substrate, thus forming an intermediate E3-Ub.…”