Proteins ubiquitin-tagged

Ubiquitin tags proteins for protein degradation. The ubiquitination requires three different enzymatic activities, a ubiquitin-activating enzyme (El), a ubiquitin-conjugating enzyme (E2 or Ubc) and a ubiquitin ligase (E3). The action of all three enzymes leads to the establishment of a poly-ubiquitin chain on target proteins which are then recognized and proteolyzed by the 26S proteasome. 

As only the 26S holoenzyme, but not the 20S-base complex degrades ubiquitylated proteins (Glickman et al. 1998a Thrower et al. 2000), it appears that recognition, and binding of ubiquitin-tagged substrates is mediated by the eight subunits of the lid subcomplex. 

The rate of protein degradation also differs from enzyme to enzyme and depends on the conditions in the cell protein half-lives vary from a few minutes to many days. Some proteins are tagged for degradation in pro-teasomes (discussed in Chapter 28) by the covalent attachment of ubiquitin (recall the case of cyclin see Fig. 12-44). Some proteins are synthesized as inactive forms, or proenzymes, that become active only when a proteolytic event removes an inhibitory sequence in the proenzyme. 

A number of different proteolytic systems are thought to be responsible for the degradation of soluble proteins in the cytoplasm of eukaryotic cells. One of the best understood is that which involves ATP and the protein ubiquitin. Ubiquitin is a small protein of only 76 residues. It occurs universally in eukaryotic cells and is highly conserved in sequence only three residues distinguish the ubiquitin in yeast and humans. The covalent attachment of ubiquitin to proteins is thought to tag them for subsequent hydrolysis by cellular proteases. 

Ubiquitin-tagged proteins are then attacked by cytosolic ATP-dependent proteases that hydrolyze the targeted protein, releasing the ubiquitin for further rounds of protein targeting. 

Distinct from the lysosomal pathway are cytosolic mechanisms for degrading proteins. Chief among these mechanisms is a pathway that includes the chemical modification of a lysine side chain by the addition of ubiquitin, a 76-residue polypeptide, followed by degradation of the ubiquitin-tagged protein by a specialized proteolytic machine. Ubiquitination is a three-step process (Figure 3-13a) ... 

This process is repeated many times, with each subsequent ubiquitin molecule being added to the preceding one. The resulting polyubiquitin chain is recognized by a proteasome, another of the cell s molecular machines (Figure 3-13b). The numerous proteasomes dispersed throughout the cell cytosol proteolytically cleave ubiquitin-tagged proteins in an ATP-dependent process that yields short (7- to 8-residue) peptides and Intact ubiquitin molecules. 

Proteasome Large complex that degrades ubiquitin-tagged proteins Protein turnover... 

Another protein modification, which occurs through a three-enzyme complex similar to that required for ubiquitin addition, is SUMOylation. SUMO stands for small ubiqutin-like modifier, and when proteins are tagged with SUMO their activites are altered (either positively or negatively, depending on the protein). SUMOylation presents yet another means of fine-tuning existing regulatory systems. 

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