Selective protein degradation: A journey's end within the proteasome

A protein's life inside a cell is usually terminated by the action of proteases that hydrolyse the polypeptide to small peptides or free amino acids. Many proteolytic enzymes are specific for only a few protein substrates, or they mediate highly specialized functions. Promiscuous proteases with broad specificities, however, are generally seques-tered and reside within specialized organelles known as lysosomes or vacuoles. Such compartmentalization is vital , as constitutively active, free proteases with broad specificities would be disastrous for proteinaceous cellular companions. The ubiquitin/proteasome system stands out from the nonlysosomal proteolytic systems because it has the capacity to degrade almost any protein but generally remains a harmless neighbor of intracellular proteins. A number of exciting discoveries in various fields have finally brought this system into the limelight (reviewed by Ciechanover, 1994; Hochstrasser, 1995). Ubiquitin/proteasome-mediated degradation was recently found to be instrumental in the regulation of a wealth of diverse cellular functions, such as DNA repair, cell cycle progression, signal transduction, transcription, and antigen presentation. A major clue as to how this degradation system operates came from the recently reported crystal structure of the proteasome (L0we et al., 1995). Several implications of these findings will be addressed below. Protein Targeting The lifespan of intracellular proteins can differ by several orders of magnitude. Structural proteins or proteins that are constitutively required are usually long-lived. In contrast , key regulatory proteins are often rapidly degraded. Their degradation, which can be precisely timed and regulated , offers the possibility of an instant switch from one functional cellular program to another. Recent examples of regulatory proteins that are turned over by the ubiquitin/ proteasome pathway are the transcription factors MAT~2 and GCN4 from yeast, the c-jun gene product, a segment of the precursor of the p50 subunit of NF-KB, IKB, the tumor suppressor protein p53, the Mos kinase, cyclins, inhibitors of cyclin-dependent kinases, and the ~ subunit of a trimeric G protein (reviewed by Jentsch, 1992; Cie-chanover, 1994; Hochstrasser, 1995). Moreover, the ubi-quitin/proteasome system also detects and eliminates abnormal proteins such as misfolded proteins or proteins that would otherwise be part of a larger complex but fail to find their partners. The challenge for this pathway is to identify and destroy from a large pool of proteins only those whose degradation is desired. Proteins are assumed to bear specific degradation signals analogous to those that target proteins to certain organelles or compartments. However, proteolytic signals are …