br Ubiquitination and deubiquitination pathways Ubiquitinati
Ubiquitination and deubiquitination pathways Ubiquitination is a part of the post-translational modification (PTM) process. Ubiquitination affects proteins in various ways, but its main functions are to signal protein degradation via the 26S proteasome, modify cellular location of proteins, affect protein activity, and promote or prevent protein-protein interaction . Ubiquitination is a process in which ubiquitin-tagged target proteins are degraded by means of the proteasomal system, thereby determining the fate of the target proteins (Fig. 2) . The multisubunit 26S proteasome consists of one 20S core complex for proteolysis and two 19S regulatory complexes for protein recognition . Proteasome-mediated ubiquitination involves consecutive actions in which three catalytic SBE 13 HCl receptor (ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3)) participate . Initially, E1 stimulates ubiquitin via an ATP-dependent activity by generating a thiol ester bond between the carboxyl terminus of ubiquitin and the cysteine residue of E1 , . The E1-activated ubiquitin is then transferred to a target protein through the action of E2 . Finally, E3 is promoted to catalyze the ligation of ubiquitin to a lysine residue of the target protein (Fig. 2) . The E3 proteins can be broadly categorized on the basis of their catalytic domains, which include the really interesting new gene (RING) and homologous to E6-AP carboxyl terminus (HECT) domains , . RING domain E3 ligases act as a bridge between E2 and the target protein by directly transferring ubiquitin to the target protein, whereas the HECT domain E3 ligases proceed in a series in which ubiquitin from E2 is first transferred to E3 . A target protein with attached ubiquitin can exhibit monoubiquitination, multiubiquitination, or polyubiquitination, and each of those types determines its cellular functions . Monoubiquitination acts on protein transport, DNA repair, endocytosis virus budding, nuclear export, and histone regulation, while multiubiquitination influences endocytosis . Polyubiquitination is involved in degradation through the 26S proteasome and regulation of cellular functions of target proteins , . Polyubiquitination relies on the seven lysine residues of ubiquitin (K6, K11, K27, K29, K33, K48, and K63) . Usually, K48-linked polyubiquitination regulates proteasome-dependent degradation of target proteins, whereas K63-linked polyubiquitination affects cellular functions such as endocytosis, DNA repair, and signaling activation , . Balanced maintenance of ubiquitinated protein is enabled by deubiquitination , and deubiquitination is aided by DUBs, which have a key role in cleaving ubiquitin chains . In addition, deubiquitination is associated with a DUB cysteine protease, which denotes the presence of a catalytic activity residue . Catalytic activity of DUBs separates the isopeptide bond between the glycine site of ubiquitin and the lysine site of the target protein . Based on their features, DUBs can be categorized into at least seven subfamilies: ubiquitin-specific protease (USP), ubiquitin C-terminal hydrolases protease (UCH), Machado-Joseph disease protein domain protease (MJD), ovarian tumor protease (OTU), Jab1/Pab1/MPN metallo-enzyme motif protease (JAMM), monocyte chemotactic protein-induced protease (MCPIP), and permutated papain fold peptidase of dsDNA viruses and eukaryotes (PPPDE) subfamilies . The USP, UCH, OTU, MJD, MCPIP, and PPPDE subfamilies contain cysteine peptidase activity. Only the JAMM subfamily includes zinc metalloisopeptidase activity , . The USP subfamily represents approximately 55% of all DUB enzymes; thus USP is considered the largest DUB subfamily . Various DUBs cleave the attachment of ubiquitin on ubiquitinated target proteins, thereby regulating cellular homeostasis. Therefore, the regulation of DUBs for ubiquitinated target proteins can determine cell fate.