Ubiquitin E3 Ligases

Ubiquitin E3 ligases (EC 6.3.2.19) attach ubiquitin molecules onto lysine residues of proteins in order to target the protein for a specific cellular process, such as proteasomal degradation or an alteration in subcellular localization. In addition to the specific ubiquitin ligases such as MDM2, E3A and anaphase-promoting complex (APC), many other proteins also contain domains that possess ubiquitin ligase activity. Almost all known ubiquitin E3 ligases contain one of three domains: a HECT, RING or A20-type zinc finger domain. Hundreds of E3 ligases have been identified so far, and their relative abundance in comparison to E1 and E2 enzymes is thought to confer specificity to the process of ubiquitination.

Ubiquitin ligases function in a complex with an E1-activating enzyme, an E2-conjugating enzyme and an E3 ubiquitin ligase. Using ATP, E1 activates the ubiquitin molecule and transfers it to E2. E2 interacts with E3 partners to transfer the ubiquitin moeity to the target protein. Generally multiple ubiquitin molecules are attached to a protein, in a process known as polyubiquitination, but the addition of single ubiquitin molecules ('monoubiquitination') may also occur within cells.

The ubiquitin ligase MDM2 is best known for its negative regulation of the tumor suppressor p53. It does this in two ways: by binding the N-terminal of p53 and inhibiting transcriptional activation; and by targeting p53 for degradation by the 26S proteasome. The latter is accomplished by polyubiquitination of p53, a consequence of MDM2's E3 ubiquitin ligase activity. Due to its inhibition of tumor suppressor activity, MDM2 is considered to be an oncoprotein, and therefore a cancer target. MDM2 may also ubiquitinate itself, though this can be reversed by the activity of USP7 (ubiquitin-specific protease 7). When DNA damage is evident, however, MDM2 is phosphorylated by ATM kinase; this lowers its affinity for USP7, permits its proteasomal degradation, and enables p53-mediated DNA repair.

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Ubiquitin E3 Ligase Gene Data