• 2018-07
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  • 2019-04
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  • br Ubiquitin ligases Ubiquitin ligases are categorized into


    Ubiquitin ligases Ubiquitin ligases are categorized into different A-803467 for 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]. Multi-subunit RING-type E3 ligases are exemplified by the CULLIN-RING-ligase (CRL) and the anaphase-promoting complex/cyclosome (APC/C) [19]. CRLs constitute the biggest family of other multi-component E3 ligases. These consist of a cullin scaffold protein (CULLIN 1, 2, 3, 4A, 4B, 5, 7), a substrate receptor, an adaptor, and a RING domain protein for E2 enzyme recruitment. A large body of evidence suggests that CRLs share a similar molecular architecture, where substrates are recruited at the N-terminal regions of the cullins, which comprise of an adaptor protein and a substrate receptor [24], [25]. For the well-characterized example of CULLIN1, the adaptor protein is SKP1, which recruits numerous substrate receptors (i.e., the F-box proteins). SKP1 can interact with both CULLIN1 and CULLIN7, while CULLIN2 and CULLIN5 utilize the elongin B/C adaptor proteins to recruit the substrate receptors; a family of proteins, which is named suppressor of cytokine signaling/elongin BC (SOCS/BC)-box-protein. CULLIN3 is unique; it utilizes a BTB domain-containing protein that can function both as an adaptor and a substrate receptor. CULLIN4A uses the adaptor protein DNA damage-binding protein-1 (DDB1), which in turns binds to substrate receptor proteins such as the DDB1 and CUL4 associated factors (DCAFs). The biological function of the cullins is involved in various cellular processes; these include cell cycle, signaling transduction, cell proliferation and survival, and DNA damage response [24]. The third class of E3 ligases is that of the RBR E3 ligases, which consists of a RING1, an intermediate RING (IBR), and a RING2 domain (Fig. 1). These ligases use a unique mode of catalyzing the ubiquitin transfer by combining both the RING-type and HECT-type E3 ligase mechanisms. Similar to classical RING-type ligases, these recognize the E2 conjugated ubiquitin by the RING1 domain and form a HECT-like intermediate by accepting the ubiquitin to the cysteine of the RING2 domain. The ubiquitin is finally transferred to the substrate by the RING2 [26].
    Ubiquitin ligases in B-cell lymphoid malignancies