Ubiquitin E3 Ligases

Supporting information

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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Gene Species Gene Symbol Gene Accession No. Protein Accession No.
MDM2 Human MDM2 NM_006880 Q00987
Mouse Mdm2 NM_010786 P23804
Rat Mdm2 NM_001108099 NP_001101569
SKP2 Human SKP2 NM_005983 Q13309
Mouse Skp2 NM_145468 Q9Z0Z3
Rat Skp2 NM_001106416 NP_001099886

Literature for Ubiquitin E3 Ligases

p53 Life Science Poster

Written by Christopher J. Brown et al, this poster highlights the main strategies that may be utilized to reactivate p53, that is found to be frequently mutated and inactivated in tumors. It focuses on small molecules and peptides which act to stabilize p53 and rescue wild-type activity. Compounds available from Tocris are listed.

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p53 Life Science Poster
Programmed Cell Death Life Science Poster

Written by Bram van Raam & Guy Salvesen, this poster summarizes the signaling pathways involved in apoptosis, necroptosis and cell survival following death receptor activation, and highlights the influence of the molecular switch, cFLIP, on cell fate.

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Programmed Cell Death Life Science Poster

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Programmed Cell Death

Written by Bram van Raam and Guy Salvesen

Programmed Cell Death Life Science Poster

Our Programmed Cell Death poster gives a summary of the signaling pathways involved in apoptosis, necroptosis and cell survival. Request copy or view PDF today.

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The p53 Tumor Suppressor Response

Written by Christopher J. Brown et al

p53 Life Science Poster

A summary of the main strategies for the reactivation of p53, including small molecules and peptides, which act to stabilize p53 to rescue wild-type activity. Request copy today.

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