Hect domain family

Schwarz, S. E., Rosa, J. L. and Scheffner, M. Characterization of human hect domain family members and their interaction with UbcH5 and UbcH7. J Biol Chem 1998, 273, 12148-54. 

After E2/ubiquitin thiol ester formation, the ubiquitin must be transferred to the substrate, which is sometimes another ubiquitin. An E3 is usually required for this reaction in vitro, and is always required in vivo. There are three known types of E3s the RING domain, HECT domain, and U-box (UED2 homology) families. RING and U-box E3s act as bridging factors for E2s and substrates, but HEGT E3s use a different mechanism, adding an extra step to the pathway (Section 5.6.3.3). 

Fig. 1. A schematic diagram outlining the hierarchic structure of the ubiquitin system. In an ATP-dependent manner a thioester bond is formed between the C-terminus of ubiquitin and an internal cystein residue of the ubiquitin-activating enzyme. Subsequently, ubiquitin is transferred to a member of the family of ubiquitin-conjugating enzymes, which are also able to form a thioester bond with ubiquitin. The third class of enzymes, the ubiquitin ligases, direct ubiquitin to the proteolytic substrates. Different families of this class of enzymes are known, some of which are also able to form a thioester intermediate with ubiquitin (HECT-domain ligases). The final ubiquitin-substrate linkage is an isopeptide bond between the C-terminus of ubiquitin and internal lysine residues in the substrate proteins...

The discovery of this family of E3 enzymes started from the studies on the targeted degradation of the p53 tumor suppressor protein. Ubiquitinylation and degradation of p53 can be mediated by the papillomavirus E6 oncoprotein (see below) in collaboration with a further protein, E6-AP (E6 associated protein). E6-AP was the first member of a large family of E3 enzymes, the Hect (homologous to E6-AP C-terminus ) domain family. These proteins contain an essential active site Cys residue near the C-terminus and one or several WW domains ( see Chapter 8.2.6). 

Based on common structural features, E3 enzymes are classified into two families, the Hect domain E3 enzymes and the RING finger E3 enzymes. 

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