Protein Degradation and the Ubiquitin System Proteolysis (protein degradation) is mediated by proteases, which range from relatively small monomeric proteins to large multisubunit proteases called protea-somes. For a very long time, and despite some evidence to the contrary, most intracellular proteins were thought to be long-lived. This assumption survived nearly intact until the 1980s, when 2 complementary sets of discoveries were made, largely by 2 groups, the laboratory of Avram Hershko at the Technion (Haifa, Israel) and my laboratory, then at Massachusetts Institute of Technology (Cambridge). Through the elegant use of biochemical fractionation and enzymology, Hershko and cowork-ers discovered in 1978-1980 that some proteins added to a mammalian cell extract became covalently conjugated to a small (76-residue) protein called ubiquitin, and that ubiquitylated proteins were destroyed by an aden-osine triphosphate (ATP)-dependent protease in the cell extract.15 (This protease was characterized by several laboratories much later, in the 1990s, and is now called the 26S proteasome.6) In 1981-1983, Hershko and co-workers identified a set of enzymes termed E1, E2, and E3 that mediate the conjugation of ubiquitin and thereby confer short half-lives on proteins that become ubiquitylated.1
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