Ubiquitin Ubiquitinylation Function

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 papilloma virus 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-ter-minus ) domain family. These proteins form a ubiquitin-E3 intermediate and then transfer the ubiquitin to lysine side chains of the substrate protein. They contain an essential active site Cys residue near the C-terminus and one or several WW domains (see Chapter 8.2.6). Fig. 2.11 illustrates schematically the function of Hect -type E3 ligases on the example of the p53 ubiqutiniylation. 

The binding of ubiquitinylated substrates requires the 19S complex of the proteasome, which possesses a ubiquitin binding site and several ATPase sites. It is believed that the function of the 19S particle is to recognize the ubiquitinylated protein, unfold the protein, remove the ubiquitin moiety, and transport the unfolded protein into the catalytic chamber of the 20S proteasome. 

Sumoylation is a covalent modification of proteins that is related to, but functionally distinct from ubiquitination (review Wilson and Rangasami, 2001). As in ubiquitinylation, sumoylation involves the covalent attachment of a small protein moiety, termed SUMO, to target proteins. The reactions leading to sumoylation of substrate proteins are related to those involved in ubiquitination. El- and E2 like enzymes are responsible for the attachment of the SUMO moiety to lysine residues of the target protein. As compared to ubiquitination, sumolyation is more sequence specific and requires a particular amino acids in the neighbourhood of the lysine to be modified. 

Uhiqidtination or ubiquitinylation is one biochemical post-translational modification requiring several stages to finally lead to the covalent fixing of one or several proteins of ubiquitin (8 kDa) on one or more lysins of the protein substrate. These biochemical modifications have several functions, the best known of which is the degradation of ubiquitinated protein by proteasome. 

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