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  • The modification of proteins with the small amino acid prote

    2019-12-04

    The modification of proteins with the small 76-amino Triclosan protein ubiquitin (Ub) plays a central role in many key cellular processes. Ubiquitylation of a target protein requires the concerted action of a cascade of three enzymes (Figure 1). The ubiquitin-activating enzyme (E1) catalyzes the formation of a reactive thioester bond via its active site cysteine residue and the C-terminal carboxylate of ubiquitin. Ubiquitin is then transferred to a ubiquitin-conjugating enzyme (E2), which in conjunction with a ubiquitin ligase (E3) confers substrate specificity. In this step the C-terminus of ubiquitin is coupled to the ɛ-amine of a lysine residue in the target protein, forming an isopeptide. Alternatively the C-terminus of ubiquitin is coupled to the N-terminus of ubiquitin resulting in a regular peptide bond, often refered to as linear. The modification of a protein with a single ubiquitin molecule (monoubiquitylation) has been shown to be required for internalization of cell surface receptors, such as the EGF receptor, as well as for DNA repair and regulation of transcription through modification of histones [1] Ubiquitin can also be coupled to itself via any of its seven lysine residues or its N-terminus. Multiple self-conjugations lead to the formation of polyubiquitin chains. These chains can either be linked homotypically through one specific residue in each module or heterotypically through a selection of different residues in each module, including multiple residues per chain forming a branched chain. There are at least 37 E2 and >600 E3 enzymes encoded in the human genome. Their specific pairing determines the type of chain linkage that is formed as well as which protein substrate is modified. Some homotypic chains have been well studied. Lys48-linked chains target proteins to the proteasome for degradation while Lys63-linked chains have functions in DNA repair. Lys11, Lys29 and N-terminally linked (linear) ubiquitin chains play roles in cell cycle control and signaling. The function of other linkage types is less clear, especially when it comes to heterotypic chains [1]. Ubiquitin modification is reversed by the action of deubiquitinating enzymes (DUBs), which cleave the isopeptide bond between the C-terminus of ubiquitin and the side chain of a lysine residue in a substrate or another ubiquitin module. DUBs are divided in five classes: USP, UCH, OTU, Josephin and JAMM/MPN+ proteases. Except for the JAMM/MPN+ class, which are Zn2+ metallo-proteases, all DUBs known so far are cysteine proteases. The activity of DUBs is tightly controlled. A large group of DUBs is regulated through reversible oxidation of the catalytic residue [2, 3], while the activity of OTUD5 is regulated by its phosphorylation status [4]. Approximately 100 DUBs are encoded in the human genome and for many of them specific functions Triclosan remain to be determined [5, 6]. The OTU class of DUBs shows remarkable selectivity for specific ubiquitin chains and is likely involved in chain editing or recycling of specifically linked chains []. The largest class of DUBs, the USP-class, does not exhibit significant linkage specificity but possibly function in a substrate-specific manner [8, 9]. Polyubiquitylation plays an important part in the regulation of both innate and adaptive immunity signaling pathways. The pathways that signal through tumor necrosis factor receptor, IL1 receptor, Toll-like receptor and T cell receptor are modulated by different modes of polyubiquitylation. These pathways effectively regulate the transcription factor NF-κB, which mediates the transcription of proteins involved in cell survival, proliferation, differentiation, inflammatory response, or apoptosis. Some examples of polyubiquitylation in these pathways are Lys63-polyubiquitylation of the kinase RIP, Met1-linked polyubiquitylation of NEMO, and Lys48-polyubiquitylation of IκBα and the NF-κB precursor. All these modifications have different outcomes, which together with the rest of the pathway have been extensively reviewed previously [10, 11, 12].