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Angelman Syndrome
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
The UBE3A gene has at least 16 exons that span about 100 kb and produces an mRNA of 5–8 kb size, spliced into five different mRNA types (34,35). UBE3A produces a protein called the E6-associated protein (E6AP), which acts as a cellular ubiquitin ligase enzyme. It is termed “E6-associated,” because it was first discovered as the protein able to associate with p53 in the presence of the E6 oncoprotein of the human papilloma virus, type 16 (36). The E6AP enzyme functions to create a covalent linkage (e.g., the “ligase” function) between the small ~76 amino acid ubiquitin molecule and its target protein (37). After initial ubiquitin attachment, for example, onto p53, E6AP can then add ubiquitins onto the first ubiquitin to create a polyubiquitylated substrate. Proteins modified in this way can then be targeted for degradation though the 26S proteasome complex (38,39). The E6AP is the prototype of what is termed the E3 component of the ubiquitin cycle; E1 and E2 proteins respectively activate and transfer the ubiquitin molecule to E3. The E3 is then able to bind to a target protein and transfer and ligate ubiquitin to the target (see Fig. 4). This ligation reaction occurs mainly in a catalytic region of the E3 enzyme, called the homologous to E6AP C terminus (HECT) domain (40). Most Angelman UBE3A mutations disrupt function of this region of the protein (41). Many E3 proteins (and their specific genes) have now been discovered and have distinct ways of mono- or polyubiquitylation. These proteins play a role in diverse cellular events such as DNA repair, cell cycle control, antigen presentation, chromosome organization, intracellular translocation of proteins, intracellular signaling, and apoptosis (42). Unfortunately, no clearly pathogenic target protein for UBE3A has yet been identified.
HERC6 is upregulated in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and promotes the disease progression
Published in Autoimmunity, 2022
Ling Cao, Hui Zhang, Jin Bai, Tingting Wu, Yingjuan Wang, Ning Wang, Caihong Huang
In this study, four SLE related gene sets were analysed by bioinformatics methods. After obtaining their differential genes, the upregulation gene HERC6 of SLE in the four gene sets was obtained by Venn diagram and verified. HERC6 gene was first identified in 2005, and it encodes proteins with two characteristic domains: HECT and the RCC1-like domain [33]. The HECT domain is described as a structural characteristic of ubiquitin-like (UBL) protein ligase function [34]. The RCC1 domain is involved in cell cycle, cytoplasmic transport, microtubule nucleation, nuclear membrane, and mitotic spindle formation by interacting with chromatin [35–37]. It has been suggested that HERC6 (mHERC6) is the main E3 ligase globally conjugated by ISG15 in mice [38]. But in humans, HERC5 plays a major role. There are few studies on HERC6 and autoimmunity, so this study found that HERC6 was up regulated in PBMCs of SLE patients, which was original.
Development and characterisation of SMURF2-targeting modifiers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Dhanoop Manikoth Ayyathan, Gal Levy-Cohen, Moran Shubely, Sandy Boutros-Suleiman, Veronica Lepechkin-Zilbermintz, Michael Shokhen, Amnon Albeck, Arie Gruzman, Michael Blank
Smad ubiquitination regulatory factor 2 (SMURF2) is a member of the HECT-type NEDD4 E3 ligase family. This family is characterised by the presence in the protein structure of the C2 domain (a calcium and lipid binding domain of ∼120 amino acids), several tryptophan-rich WW domains (∼40 residues long; play a role in protein–protein interactions via recognition of proline‐rich motifs in target proteins), and the catalytical carboxy-terminal HECT domain (∼350 residues). HECT domain consists of N- and C-terminal lobes connected through a flexible hinge allowing them to come together during ubiquitin transfer. The N-lobe interacts with E2, whereas the C-lobe harbours the active-site cysteine (Cys716 in SMURF2) forming the thioester bond with ubiquitin. Despite high similarities in the domain composition, NEDD4 E3s have distinct substrate repertoire and reveal distinct roles in physiological and pathobiological processes, including cancer1–4. In neoplastic diseases, SMURF2 was shown to exert both tumour-promoting and suppressor activities, depending on tumour type, stage, molecular and cellular contexts, and other still unidentified factors5.
Targeting ubiquitin protein ligase E3 component N-recognin 5 in cancer cells induces a CD8+ T cell mediated immune response
Published in OncoImmunology, 2020
Mei Song, Chao Wang, Huan Wang, Tuo Zhang, Jiuqi Li, Robert Benezra, Lotfi Chouchane, Yin-Hao Sun, Xin-Gang Cui, Xiaojing Ma
Breast cancer is the most common malignancy among women in the United States and the second most common cause of mortality among women ages 45 to 55 y.1 Estimated 249,260 new breast cancer cases were identified in the United States in 2016 and the predicted number of deaths is that year was 40,890.1 Despite the development of newer diagnostic methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis, and drug resistance are still the major problems for breast cancer. Clearly, more therapeutic modalities are needed for this most common form of cancer diagnosed in women worldwide. In an effort to identify potential “driver” genetic alterations for human breast cancer development and/or pathogenesis, we analyzed the whole-exon sequence data from the surgical tumor samples of a cohort of triple-negative breast cancer (TNBC) patients in comparison to the surrounding normal tissues.2 One of the most strikingly altered genes in over 30% of the specimens that we examined was ubiquitin protein ligase E3 component n-recognin 5 (UBR5, a.k.a., EDD), a member of the rare HECT-domain E3 ubiquitin ligase family.3