Removal of misfolded proteins from the ER is a consequential process characterized by the interaction between numerous proteins in the ER and the cytoplasm (Needham and Brodsky, 2013). To enter the ERAD pathway, the protein must be exported from the ER to the cytosol in a process called retro-translocation, also called dislocation. This retro-translocation process takes place via the same translocon in which the proteins used initially enter the ER – the Sec61 complex. This retro-translocation channel present in the ER membrane is made up of several multi-protein complexes (Zhang et al., 2015). Each complex functions around a ubiquitin ligase in the membrane, an enzyme necessary to recognize the targeted protein. Ubiquitin ligases are constituents of the ubiquitin proteasome system (UPS), a system that plays an essential role in ERAD. It is responsible for finding and destroying proteins that are damaged, defective or simply excess to requirements. The UPS uses a protein called ubiquitin to target these defective proteins in a process called ubiquitination. Say no to plagiarism. Get a tailor-made essay on “Why violent video games should not be banned”? Get the original essay The process of ubiquitination is carried out by three different enzymes: the ubiquitin-activating enzyme (E1), the enzyme conjugation of ubiquitin (E2) and ubiquitin. ligases (E3) and uses ATP as an energy source/E1 forms a high-energy thioester bond between a cysteine ​​residue present in its active site and the C-terminus of ubiquitin. This activated ubiquitin is then transferred to E2. E3 binds to the misfolded protein and aligns it in such a way that the protein can bind to the ubiquitin attached to E2. An isopeptide bond forms between the C-terminal glycine of ubiquitin and the lysine residues on the targeted protein. Several rounds of ubiquitination take place, forming a polyubiquitin chain (Nandi et al.). This polyubiquitin chain on the misfolded protein signals its degradation via the 19S capping complexes of the 26S multi-subunit proteasome. The proteasome binds and removes the polyubiquitin chain, unfolding the protein into smaller peptides. The protein is then reused for the synthesis of new proteins and the ubiquitin is recycled. Although the 26S proteasome recognizes poly-ubiquitinated proteins, the high specificity and selectivity of the UPS resides in different E3 enzymes, capable of recognizing a wide range of substrates (Wang and Maldonado). In humans, hundreds of E3s exist and are distinguished from each other by the presence of different domains - a RING-like domain (RING) or HECT. RING domains transfer ubiquitin protein from E2 directly to the targeted substrate while HECT E3 domains transfer ubiquitin from E2 to E3 and then from E3 to the substrate (Berndsen and Wolberger, 2014). Although a wide range of studies have been conducted on E3 enzymes, the mechanisms by which they act and further increase ubiquitin transfer remain to be considered (Berndsen and Wolberger, 2014). Research into how E3 ligases are regulated by interaction with different E2 enzymes and substrates could provide additional insight into E3 specificity and reveal more about E ligase binding3..