Cellular proteins, degradation

In contrast to c-Jun, phosphorylation of the tumor suppressor p53 by CSN-associated kinases targets the protein for degradation by the Ub system [35]. For p53 stability, modification on Thrl55 is most important as shown by mutational analysis [35] and by using different p53 peptides [31]. Mutation of Thrl55 to Val led to stabilization of the transiently expressed p53 mutant in HeLa as well as in HL60 cells [35]. Inhibitors of CSN-associated kinases such as curcumin [18] caused stabilization of cellular p53 followed by massive cell death [35]. 

During the past 25 years a considerable body of data has been accumulated, often to atomic resolution, on the structure and function of proteins. In contrast we know far less about the life cycle of these proteins—those processes which put a protein in the part of the cell in which it is to function and the cellular movements (if any) of this protein as it carries out its function. We know even less about those processes which eventually single out the protein for degradation. 

Hemming, M.L., Selkoe, D.J. (2005) Amyloid 3-protein is degraded by cellular angiotensinconverting enzyme (ACE) and elevated by an ACE inhibitor. J. Biol. Chem., 280,37644-37650. 

For many years, I have been interested in the problem of how proteins are degraded in cells. The dynamic state of cellular proteins (Schoenheimer, 1942) and the important roles of protein degradation in the control of cellular enzyme levels (Schimke Doyle, 1970) have been recognized for a long time, but the underlying molecular mechanisms remained unknown. A clue to an unusual mechanism was provided by observations indicating that the... 

Dietary protein is digested in the intestine, producing amino acids that are transported throughout the body. Cellular proteins are degraded at widely variable rates, ranging from minutes to the life of the organism. 

Fig. 8 Cellular protein turnover. Due to protein synthesis the nuclear and cytosolic protein pools are formed. A part of these proteins is oxidized and degraded, whereas the bulk of the proteins are degraded due to normal protein turnover. Only a small amount of oxidized proteins accumulates in aggregates...

Fig. 9 Formation of protein aggregates. Proteins are oxidized due to environmental and metabolic influences. The part of the oxidized proteins escaping degradation form initial aggregates. These become cross-linked and insoluble due to intramolecular reactions. The chemically highly reactive surface of the aggregates tends to attract more proteins, in particular oxidized ones, and a process of enlarging of the aggregates takes place. It is important to note that these aggregates disturb cellular metabolism...

The digestion of many food molecules involves hydrolysis. For example, proteins are degraded in the stomach in an acid-catalyzed reaction. Another important example is breaking the phosphate bonds of ATP (Figure 1.16). The energy obtained during this reaction is used to drive many cellular processes. 

Cathepsins are lysosomal proteases which are designed to function in an acidic milieu. Although the specific roles of each protease are not yet defined, it seems likely that extracellular proteins taken up by a cell and long-lived cellular proteins are degraded in lysosomes, while selective protein turnover related to metabolic regulation occurs in other compartments. 

Chaperones are involved at all stages of cellular metabolism, during protein biosynthesis and maturation, in protection from environmental stress, in rearrangements of cellular macromolecules during functional cycles of assembly and disassembly, and finally in targeting proteins for degradation. 

---