Journal
PROTEIN SCIENCE
Volume 15, Issue 3, Pages 647-654Publisher
WILEY
DOI: 10.1110/ps.052012306
Keywords
ubiquitir; proteasome; proteolysis; N-end rule; nitric oxide
Categories
Funding
- NIDDK NIH HHS [R01 DK039520] Funding Source: Medline
- NIGMS NIH HHS [R01 GM031530] Funding Source: Medline
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This is a personal account of the early history of ubiquitin research, by one of its protagonists. The field of ubiquitin and regulated protein degradation was created in the 1980s, largely through the complementary discoveries by the laboratory of A. Hershko (Technion, Haifa, Israel) and by my laboratory, then at MIT (Cambridge, MA). I describe the elegant insights by Hershko and his colleagues that yielded the initial understanding of ubiquitin conjugation and ubiquitin-mediated proteolysis in cell extracts, including the identification of E1, E2, and E3 enzymes. These advances were followed by a,et of interconnected discoveries in my laboratory that revealed the biology of the ubiquitin system, its necessity for the protein degradation in vivo, its specific physiological functions (in the cell cycle, DNA repair, protein synthesis, transcriptional regulation, and stress responses), the source of its selectivity (specific degradation signals in short-lived proteins), and its key mechanistic attributes, such as the polyubiquitin chain and the subunit selectivity of protein degradation. The above biological (function-based) insights produced the main discovery of the physiological regulation by intracellular protein degradation. These advances caused the enormous expansion of the ubiquitin field in the 1990s. Together with the initial discovery of ubiquitin-mediated proteolysis by Hershko and coworkers, our biological discoveries in the 1980s led to a radically changed understanding of the logic of intracellular circuits, as it became clear that the control through regulated protein d.-gradation rivals, and often surpasses in significance, the classical regulation through transcription and translation.
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