Ub-protein ligases

Physiologically, X may contribute to the removal of dopaminergic neuronal cells, when they are accidentally impaired. If so, why does parkin exist in other types of cells and tissues Probably, in these cells parkin targets a different substrate(s), termed here Y(s) , which is distinct from X for cell death-signalling. In addition, another unknown Ub-protein ligase(s) may be responsible for ubiquitinating Y and thus in AR-JP no appreciable defects... 

There are four types of Ub-protein ligases namely N-end rule E3, hect-Aomasa E3, anaphase promoting complex and phosphoprotein-ubiquitin ligase complex. The main N-end rule E3, E3a is the best characterized ubiquitin ligases. It is approximately a 200-kDa protein that binds N-end rule (Varshavsky, 1996) protein substrates that have basic, i.e. Lys, Arg, His (Type I) or bulky-hydrophobic, i.e. Trp, Phe, Tyr, Leu (Type II) N-terminal... 

Figure 23.3. Ubiquitin Conjugation. The ubiquitin-activating enzyme El adenylates ubiquitin (Ub) and transfers the ubiquitin to one of its ovm cysteine residues. Ubiquitin is then transferred to a cysteine residue in the ubiquitin-conjugating enzyme E2. Finally, the ubiquitin-protein ligase E3 transfers the ubiquitin to a lysine residue onthe target protein.

Figure 12.10 Ubiquitin proteolytic pathway. Proposed sequence of events in conjugation and degradation of proteins via ubiquitin system involves activation of ubiquitin (Ub), transfer of activated ubiquitin, conjugation of protein to ubiquitin by ubiquitin-protein ligase, usuaUy polyubiquitination, and degradation of ligated protein by 26S protease complex (proteasome)...

After the linkage of Ub to the substrate protein, a polyubiquitin (multiubiquitin) chain is often formed, in which the C-terminus of each ubiquitin unit is linked to a specific Lys residue (most commonly Lys48) of the previous Ub. The multiubiquitin-chain assembly is a processive reaction that usually requires only El, E2 and E3. However, an efficient multiubiquitination needs an additional conjugation factor termed E4 enzyme (Hoppe, 2005). Ubiquitin-protein ligases are, directly or indirectly, those that bind specific protein substrates, promote the transfer of Ub, and form a thioester intermediate to amide linkages with proteins or polyubiquitin chains. 

Fig. 2.9 Ubiquitinylation of proteins and degradation in the proteosome. Ubiquitin (Ub) is initially activated by an enzyme El, whereby the C-terminal carboxyl group of ubiquitin becomes attached to an SH group of El via a thioester bond. The activated ubiquitin is then transferred from El-Ub to the ubiquitin-conjugating enzyme, E2. Finally, the ubiquitin is covalently attached to the target protein in a reaction catalyzed by the E3 ubiquitin ligase. Re-...

EXAMPLE 6.17 A Ub ligase called APC is activated by signaling pathway-dependent phosphorylation as cells approach mitosis. This 3 enzyme catalyzes the attachment of Ub to varions proteins, including lamins that are components of the nuclear membrane. Degradation of lamins allows dissolution of the nuclear membrane, permitting release of chromatids in preparation for mitosis. 

They do this in at least two ways. First, because they contain SH2 domains, they can bind to the phosphotyrosine residues of proteins involved in the pathway. In doing this they act as competitive inhibitors of the pathway proteins that are activated by binding to these residues. Second, they contain a domain called a SOCS box. The SOCS box forms part of an 3 Ub ligase. Therefore, binding of SOCS proteins to proteins in the pathway targets them for ubiquitinylation and subsequent degradation. 

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