Components of the Ubiquitin System

Ubiquitin is a 76 residue protein found in nearly every eucaryote. It occurs either in free form or bound to other proteins. All known functions of ubiquitin are transmitted via its covalent linkage with other proteins. This serves the purpose, among others, of marking the proteins for proteolytic degradation. 

The ubiquitinylation of proteins is a complex process which involves several specific enzymatic reactions. Three sequential steps can be distinguished (fig. 2.15A)  

In an initial reaction ubiquitin is activated by forming a reactive thiolester with an SH-group of the ubiquitin-activating enzyme El. This step requires ATP and consists of an intermediate formation of ubiquitin adenylate followed by the binding of ubiquitin to a Cys residue of El in a thiolester linkage, with the release of PPi and AMP. 

In a transacylation reaction the ubiquitin moiety is transferred from El-Ub to the SH-group of the ubiquitin-carrier protein E2 to form E2-Ub. 

The third step of ubiquitinylation, the transfer of ubiquitin to the target protein, is catalyzed by a ubiquitin-protein-ligase, or E3 enzyme. In this reaction ubiquitin is linked by its C-terminal glycine in an amide isopeptide linkage to an e-NH2-group of the substrate proteins Lys residues. 

The ubiquitinylation of proteins is a complex process, which involves three sequential enzymatic reactions performed by three types of enzymes, El, E2 and E3 (Fig. 2.9). The enzymatic conjugating cascade is organized in a hierarchical way There is one El enzyme, a limited number of E2 enzymes, each of which may serve several E3 enzymes, and a much larger number of E3 enzymes (Fig. 2.10). 

Ubiquitin can be transferred to the substrate protein by two different mechanisms  

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From the viewpoint of bioinformatics, the second observation has turned out to be most useful. The identification of a ubiquitin-like domain in a protein makes it a good candidate for a new component of the ubiquitin regulatory system. In addi-... 

Many diseases have been linked to components of the ubiquitin-proteasome pathway. These diseases affect several tissues and systems of the body. Major diseases connected to ubiquitin—proteasome-mediated proteolysis are different types of cancer and numerous diseases and disorders of the brain. 

Subcellular Distribution of Components of the Ubiquitin-Proteasome System... 

Studies on JA signaling were substantially advanced with a series of research on the COI1, Coronatine Insensitive 1. This protein has an F-box motif, which has been originally found in a component of the ubiquitin—proteasome system.837 Another well-known mutant of jasmonate function is jar 1, which is impaired... 

Hofmann, K. and Falquet, L. A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems. Trends Biochem Sci 2001, 26, 347-50. 

The mechanistically and functionally complex N-end rule pathway (Fig. 2) is but one of many distinct pathways of the Ub system. The vast functional range of this system stems from the enormous diversity of its physiological substrates. In other words, it is the constitutive or conditional degradation of many specific proteins (cyclins, transcription factors, components of signal transduction pathways, damaged proteins) by ubiquitin-dependent pathways that underlies the involvement of the Ub system in just about every biological circuit in a living cell (5, 6, 9). 

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