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  • br The ubiquitin proteasome system The ubiquitin proteasome


    The ubiquitin proteasome system The ubiquitin proteasome system (UPS) plays a significant role in the regulation of cell growth and survival, in addition to maintaining cellular homeostasis. By means of the UPS, Bradykinin acetate australia can precisely and temporally degrade approximately 80% of the entire proteome. However, failure to do so results in numerous diseases, including hematological malignancies and cancer [1], [2], [3]. Protein ubiquitylation is catalyzed Bradykinin acetate australia by a three-step enzymatic cascade in which the ubiquitin is first activated by an E1 enzyme (ubiquitin-activating enzyme) and subsequently transferred to an E2 enzyme (ubiquitin-conjugating enzyme). Finally, ubiquitin is attached to a specific substrate that is selected by an E3 ubiquitin ligase that governs substrate specificity. One of the principal outputs of protein ubiquitylation is degradation via the proteasome complex. The proteasome comprises of a regulatory 19S cap complex that unfolds the substrates in an ATP-dependent manner and a catalytic 20S core complex that has proteolytic activities [1]. Proteins that are tagged by the ubiquitin chains are recognized, deubiquitylated, and unfolded by the 19S complex and subsequently fed through the inner channel of the 20S proteasome chamber, which cleaves proteins into peptides [4]. Ubiquitin contains total of eight attachment sites (seven lysine residues and the amino N-terminus) for the formation of polymeric chains [5]. Substrates can be modified at multiple lysine residues with a single ubiquitin molecule (multimono-ubiquitylation), or a single ubiquitin molecule can build a chain using ubiquitin as substrate [6]. Moreover, ubiquitin chains can be homotypic conjugates where they are elongated through the same lysine as in Lys11-, Lys48-, Lys63-linked chains or methionine (M-linked) residue, as in linear chains [6]. Lys-11-linked chains and Lys48-linked chains target proteins for proteosomal degradation [7], [8]. On the other hand, Lys-63-linked chains regulate DNA repair, endocytic trafficking, NF-κB activation, and assembling a signaling complex for mRNA translation [9], [10], [11], [12]. M-linked chains or linear ubiquitin chains play an important role in immune, inflammatory and NF-κB signaling [13], [14], [15]. The significance and the roles of Lys6-, Lys27-, Lys29-, Lys33- linked chains are still poorly understood although, recently, they have been implicated in DNA repair, trans-Golgi trafficking, and mitochondria damage [16], [17].
    Ubiquitin ligases Ubiquitin ligases are categorized into different classes based on their specific structural configuration and the composition of subunits—HECT (homologous to E6-AP1 (E6-associated protein 1) carboxy-terminus)-type, RING (really interesting new gene)-finger-type, U-box-type, or RING-in-between-RING (RBR)-type (Fig. 1). The HECT-type E3 ligases are the only ones that demonstrate intrinsic catalytic activity, as they receive the ubiquitin from an E2 enzyme and transfer it to the substrate [18]. HECT-type E3 ligases are the first family of E3 ligases that have been described and consist of ∼30 HECT domain E3 ligases in mammals. They play important roles in several biologic areas, including protein trafficking, cell growth and survival, immune regulation, and many others [19]. The N-terminus of the HECT-type E3 ligases mediates substrate targeting, while the C-terminus contains the conserved HECT domain, which interacts with the E2 and contains an active cysteine that accepts the ubiquitin-moiety. The topology of the HECT-type E3s with the E2s depends on the status of the ubiquitin transfer of E2 and the non-covalent interaction with all N-terminus, C-terminus, E2 and ubiquitin [20], [21]. The RING-finger and the U-box- type E3 ligases act as a scaffold protein to bridge an E2 enzyme and a substrate proximally for ubiquitin conjugation (Fig. 1). The RING-finger-type E3 ligases are generally thought to be the biggest family of ligases and contain a Zn2+-coordinating domain with spaced cysteine and histidine residues, facilitating E2-dependent ubiquitylation [22]. The RING finger ubiquitin ligase family functions either as a monomer, dimer, or a multi-subunit complex. Homodimerization and/or heterodimerization usually occurs through the RING finger domain [23].