Jin, J., Li, X., Gygi, S.P. & Harper, J.W. Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature 447, 1135-1138

Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 07/2007; 447(7148):1135-8. DOI: 10.1038/nature05902
Source: PubMed


Modification of proteins with ubiquitin or ubiquitin-like proteins (UBLs) by means of an E1-E2-E3 cascade controls many signalling networks. Ubiquitin conjugation involves adenylation and thioesterification of the carboxy-terminal carboxylate of ubiquitin by the E1-activating enzyme Ube1 (Uba1 in yeast), followed by ubiquitin transfer to an E2-conjugating enzyme through a transthiolation reaction. Charged E2s function with E3s to ubiquitinate substrates. It is currently thought that Ube1/Uba1 is the sole E1 for charging of E2s with ubiquitin in animals and fungi. Here we identify a divergent E1 in vertebrates and sea urchin, Uba6, which specifically activates ubiquitin but not other UBLs in vitro and in vivo. Human Uba6 and Ube1 have distinct preferences for E2 charging in vitro, and their specificity depends in part on their C-terminal ubiquitin-fold domains, which recruit E2s. In tissue culture cells, Uba6 is required for charging a previously uncharacterized Uba6-specific E2 (Use1), whereas Ube1 is required for charging the cell-cycle E2s Cdc34A and Cdc34B. Our data reveal unexpected complexity in the pathways that control the conjugation of ubiquitin, in which dual E1s orchestrate the charging of distinct cohorts of E2s.

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    • "In the human genome two E1 enzymes, 20–30 E2 enzymes and a few hundred substrate-specific E3 enzymes have been identified, with the cascade's increased complexity from conjugation (Jin et al. 2007) to poly-ubiquitination (Sadowski and Sarcevic 2010) allowing for diverse substrate-ubiquitin structures directing proteins to different fates. Several muscle-specific E3s exist: Muscle Ring Finger 1 (MuRF1) regulates the dissociation and degradation of myosin light chains 1 and 2, myosin binding protein C and cardiac Troponin I (Cohen et al. 2009; Kedar et al. 2004), MuRF3 ligase ubiquitinates soluble myosin (Fielitz et al. "
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    • "In most other tissues, FAT10 is not expressed unless the pro-inflammatory cytokines IFNc and TNFa are present (Liu et al., 1999; Raasi et al., 1999). FAT10 needs no processing, but is activated and conjugated by the constitutively expressed E1 and E2 enzymes UBA6 and USE1, respectively (Aichem et al., 2010; Chiu et al., 2007; Jin et al., 2007; Pelzer et al., 2007). Potential E3 ligases and deconjugating enzymes have not yet been identified. "
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    Full-text · Article · Sep 2014 · Journal of Cell Science
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    • "Our study suggests that DC-UbP binds to USP5 on the tandem UBA domains, implying that binding of DC-UbP to USP5 potentially regulates the deubiquitination process. On the other hand, the UbE1 enzyme utilizes ATP to activate the terminal glycine residue of Ub generating a covalent thioester linkage between ‘activated’ Ub and the UbE1 enzyme itself [44]. The UbE1 protein is mainly comprised of three domains, the adenylation domain that binds ATP and Ub, the catalytic cysteine domain that binds activated Ub, and the C-terminal Ub-fold domain (UFD) that recruits specific E2 conjugating enzymes [27]. "
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