Structure and function of HECT E3 ubiquitin ligases and their role in oxidative stress

Abstract

Ubiquitination is a modification after protein transcription that plays a vital role in maintaining the homeostasis of the cellular environment. The Homologous to E6AP C-terminus (HECT) family E3 ubiquitin ligases are a kind of E3 ubiquitin ligases with a C-terminal HECT domain that mediates the binding of ubiquitin to substrate proteins and a variable-length N-terminal extension. HECT-ubiquitinated ligases can be divided into three categories: NEDD4 superfamily, HERC superfamily, and other HECT superfamilies. HECT ubiquitin ligase plays an essential role in the development of many human diseases. In this review, we focus on the physiological and pathological processes involved in oxidative stress and the role of E3 ubiquitin ligase of the HECT family.

Signaling Pathways Regulated by UBR Box-Containing E3 Ligases

“…The HECT domain consists of two different lobes, the N-terminal lobe (N-lobe) and C-terminal lobe (C-lobe), connected by a flexible linker. The N-lobe is responsible for binding the E2s, whereas the C-lobe bears the catalytic cysteine that accepts ubiquitin from the E2 to generate an E3–ubiquitin complex [ 48 , 49 ]. Therefore, unlike RING E3s, HECT E3s must be physically conjugated with ubiquitin before transferring the ubiquitin to the substrate.…”

“…Therefore, unlike RING E3s, HECT E3s must be physically conjugated with ubiquitin before transferring the ubiquitin to the substrate. The HECT domain of UBR5 is present in its extreme C-terminus, and its catalytic cysteine is Cys2768 [ 48 ].…”

Insights Into the Biological Role of NEDD4L E3 Ubiquitin Ligase in Human Cancers

“…To date, there have been more than 600 E3s in the human genome, which are mainly sorted into three categories: really interesting new gene (RING) finger family E3s, the RING-between-RING (RBR) family E3s, and homologous to the E6-AP C-terminus (HECT) family E3s ( 6 ). HECT family E3s have an active site for cysteine, where cysteine binds to ubiquitin for an intervening thioester prior to its substrate ( 7 ). Specific recognition of substrates is based on the nonconservative N-terminus of HECT family E3s ( 8 ).…”

Redox regulation of DUBs and its therapeutic implications in cancer

“…The ubiquitin-proteasome system (UPS) regulates protein turnover of their substrates implicated in different cellular processes including the cell cycle, DNA repair, and cell apoptosis [ 22 , 23 ]. Importantly, the enzymes responsible for ROS production are also known to undergo 26S proteasomal degradation [ [24] , [25] , [26] ]. However, the regulation of deubiquitinating enzymes (DUBs) that reverse the process of protein ubiquitination of ROS-generating enzymes is an equally important process that has not been given much attention.…”