Ubiquitination, or ubiquitylation, is a common process of post-translational modification, which transfers ubiquitin into the target protein for a wide range of cellular effects in eukaryotes. As shown in Figure 1, ubiquitin is activated in an ATP-dependent manner by a ubiquitin-activating enzyme (E1), and it is transferred to a ubiquitin-conjugating enzyme (E2) that, with the help of a ubiquitin-protein ligase (E3), attaches ubiquitin to the target protein through the epsilon-amino group of a lysine residue. E3 is particularly responsible for the specific recognition of the target protein in a pathway. The attached ubiquitin chain is lengthened by the E2 and E3, sometimes with the help of an additional factor, i.e., the ubiquitin-chain elongation factor (E4).

* It is known that each ubiquitin-like modifier protein has a single dedicated E1. (Pickart and Eddins, 2004)^[1]
E3DB provides UBE1 or UBA1 proteins as E1 enzymes for each E3-dependent ubiquitination pathway.

Glossary

Ubiquitination pathway

A pathway of ubiquitin to the target protein via enzyme cascades.

Ubiquitin: A small protein consisting of 76 amino acid residues, well conserved in eukaryotic cells.
E1: ubiquitin-activating enzyme.
E2: ubiquitin-conjugating enzyme.
E3: ubiquitin-protein ligase.
E4: ubiquitin-chain elongation factor.
DUB: deubiquitinating enzyme.
Target protein: protein substrate targeted by ubiquitination.

E3 domain

E2-binding domains that catalyze ubiquitination.

The families of E3 proteins are generally classified by the E2-binding domains. (Ardley and Robinson, 2005)^[2]
E3 proteins contain one of the two following domains:
    - HECT (Homologous to the E6-AP Carboxyl Terminus) domain
    - RING (Really Interesting New Gene) domain

Two other domains are closely related to the RING domain:
    - U-box domain
    - PHD domain

Ubiquitin structure

Distinct forms of ubiquitins that are attached to the target protein.

Monoubiquitination: addition of a ubiquitin to a single lysine residue in the target protein.
Oligoubiquitination: addition of a few ubiquitin molecules (generally, at most three) to a single lysine residue in the target protein.
Multiubiquitination: addition of multiple ubiquitin molecules to multiple lysines in the target protein.
Polyubiquitination: addition of a ubiquitin chain to a single lysine residue in the target protein.
Ubiquitin chain: a chain of ubiquitin molecules (generally, at least four) that are linked by isopeptide bonds between the C-terminal glycine of ubiquitin and the epsilon-amino group (most commonly K48) of the ubiquitin. Ubiquitin is known to have seven sites (K6, K11, K27, K29, K33, K48, and K63) for ubiquitin chains. (Peng et al, 2003)^[3]

* There is no agreement on the use of these terms. For example, in some articles, 'multiubiquitination' is also used as 'polyubiquitination' with a similar meaning. Similarly, 'oligoubiquitination' is used with 'monoubiquitination'. We follow the terms used in (Welchman et al, 2005)^[4]

Human disease

E3-dependent human diseases.

E3s are known either to induce diseases directly, or to cause them indirectly by interacting with disease-induced proteins. Such diseases include cancers, genetic disorders, and viral infections.

References

[1] Pickart C.M. and Eddins M.J. (2004). Ubiquitin: structures, functions, mechanisms. Biochim. Biophys. Acta 1695, 55-72. (PMID: 15571809)

[2] Ardley HC, Robinson PA. E3 ubiquitin ligases. Essays Biochem. 2005;41:15-30. (PMID: 16250895)

[3] Peng J, Schwartz D, Elias JE, Thoreen CC, Cheng D, Marsischky G, Roelofs J, Finley D, Gygi SP. A proteomics approach to understanding protein ubiquitination. Nat Biotechnol. 2003 Aug;21(8):921-6. (PMID: 12872131)

[4] Welchman RL, Gordon C, Mayer RJ., Ubiquitin and ubiquitin-like proteins as multifunctional signals. Nat Rev Mol Cell Biol. 2005 Aug;6(8):599-609. Review. (PMID: 16064136)