Regulation of enzyme levels by proteolysis: the role of pest regions.

Enzymes can be regulated in a variety of ways. Readily reversible mechanisms, such as phosphorylation, are frequently used by cells to control metabolic pathways. Less often, enzyme levels are regulated by changing the rate at which the protein is destroyed. Although these changes, too, are reversible through protein synthesis, large variations in enzyme concentration can be produced in very short periods of time by combinations of transcriptional control, translational control and rapid degradation. We recently examined the primary sequences of proteins whose intracellular half-lives are less than two hours. With a single exception, each short-lived protein contains one or more regions rich in proline (P), glutamic acid (E), serine (S) and threonine (T). These PEST regions range in length from 12 to 60 residues, and they are often flanked by possibly charged amino acids. Similar inspection of 35 more stable, structurally characterized proteins revealed only three weak PEST regions. All PEST proteins appear to be important regulatory molecules, and their fast turnover surely reflects a metabolic requirement for rapid changes in their concentrations. Known PEST proteins include oncogene products, key enzymes and components of signal pathways. In addition, there are a number of PEST-containing proteins that are suspected of being rapidly degraded. These proteins include Drosophila homeotic proteins (e.g., notch, snake, caudal, ftz and even-skipped) and a host of yeast cdc mutants. PEST regions, which target the molecules containing them for destruction, thus appear to be widely distributed among metabolically unstable proteins.