Abstract
Owing to the intensive research activity on protein synthesis, little attention was paid in the 1950s and 1960s to protein degradation. However, work by my group and others between 1970 and 1990 led to the identification of the ubiquitin-dependent degradation system. We found that this system contains three types of enzymes: E1 ubiquitin – activating enzyme, E2 ubiquitin – carrier enzyme and E3 ubiquitin – protein ligase. The sequential action of these enzymes leads to conjugation of ubiquitin to proteins and then in most cases to their degradation. This review briefly tells the story of how this pathway was discovered describing the main findings that during the years allowed us to draw the complex picture we have now.
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Abbreviations
- TAT:
-
tyrosine aminotransferase
- APF-1:
-
ATP-dependent proteolysis factor 1
- cdk:
-
cyclin-dependent kinase
- MPF:
-
M phase-promoting factor
- APC/C:
-
anaphase-promoting complex/cyclosome
- SCF:
-
Skp1-Cuilin1-F-box protein *Nobel Lecture 2004, © The Nobel Foundation 2004
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Acknowledgements
In experimental sciences, including biochemistry, discoveries are not made by a single person, but require the assistance of dedicated research teams and the help of friends, colleagues and collaborators. In my laboratory at the Technion, Haifa, I was very fortunate to receive devoted help, at different times over a period of more than 30 years, from Dvora Ganoth, Hanna Heller, Esther Eytan, Sarah Elias, Clara Segal and from my wife, Judith Hershko. Among my former graduate students, Aaron Ciechanover did tremendous work in the exciting times of the discovery of ubiquitin-protein ligation 25 years ago. Subsequently, many other graduate students (too many to list here) did very important work on the basic biochemistry of the ubiquitin system and more recently, on some roles of this system in cell cycle control. Out of my several friends, collaborators, mentioned in this paper, Irwin Rose had a very special role. My association with Ernie started with a sabbatical year in his laboratory in Fox Chase Cancer Center, Philadelphia, in 1977–1978 (see also accompanying biography). During this year, I continued to work on the initial fractionation of the reticulocyte system and the purification of ubiquitin, which we started in Haifa. In the following summer of 1979, Ernie invited me back to his laboratory, together with my graduate student Aaron Ciechanover and research assistant Hanna Heller. When we got there we already knew, from work done in the Haifa lab, that ubiquitin bound to proteins in an ATP-dependent process. However, the discovery that a covalent amide bond is formed between ubiquitin and the substrate protein was made together with Ernie Rose in that summer in Philadelphia. A group picture, taken at the end of this memorable summer of 1979 at Fox Chase Center, included the people involved (Figure 6). The results of this summer's work were reported in Hershko et al.16 This Review was possible because of kind help of the Nobel Foundation in Stockholm, http://nobelprize.org (© The Nobel Foundation 2004).
At the end of summer of 1979 in Fox Chase Cancer Center, Philadelphia. Seated left to right: Avram Hershko, Sandy Goldman, Jessie Warms, Hanna Heller, Standing left to right: Zelda Rose, Arthur Haas, Aaron Ciechanover, Mary Williamson, Irwin Rose, Keith Wilkinson and Leonard Cohen (last three people standing on the right side not identified)
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Nobel Lecture 2004, © The Nobel Foundation 2004
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Hershko, A. The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ 12, 1191–1197 (2005). https://doi.org/10.1038/sj.cdd.4401702
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