Ubiquitin–Proteasome Machinery: Cells Garbage Disposal



Proteins are cells building blocks with a highly dynamic existence. Rates of synthesis and degradation dictate cellular protein levels at any given moment. Many proteins such as transcription factors or signaling molecules are rapidly degraded (min), while structural proteins have very slow turnover rates (days). Similarly, damaged or improperly folded proteins are rapidly degraded. Two major cellular pathways operate to mediate the degradation of cellular proteins. One involves the ATP-dependent ubiquitin–proteasome pathway and the other involves the non-ATP-dependent proteolysis that occurs in the lysosome. In this chapter, the discovery, structure–function, and disease resulting from impaired ubiquitin–-proteasome-mediated protein degradation are discussed.


Proteasome Ubiquitin ATP-dependent degradation Cells garbage disposal 


  1. 1.
    Hershko, A., & Tomkins, G. M. (1971). Studies on the degradation of tyrosine aminotransferase in hepatoma cells in culture. The Journal of Biological Chemistry, 246, 710–714.PubMedGoogle Scholar
  2. 2.
    Ciechanover, A., Hod, Y., & Hershko, A. (1978). A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochemical and Biophysical Research Communications, 81, 1100–1105.CrossRefGoogle Scholar
  3. 3.
    Hershko, A., Ciechanover, A., & Rose, I. A. (1979). Resolution of the ATP-dependent proteolytic system from reticulocytes: A component that interacts with ATP. Proceedings of the National Academy of Sciences, 76, 3107–3110.CrossRefGoogle Scholar
  4. 4.
    Hershko, A., Ciechanover, A., Heller, H., Haas, A. L., & Rose, I. A. (1980). Proposed role of ATP in protein breakdown: Conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis. Proceedings of the National Academy of Sciences, 77, 1783–1786.CrossRefGoogle Scholar
  5. 5.
    Ciechanover, A., Elias, S., Heller, H., & Hershko, A. (1982). “Covalent affinity” purification of ubiquitin-activating enzyme. The Journal of Biological Chemistry, 257, 2537–2542.PubMedGoogle Scholar
  6. 6.
    Hershko, A., Heller, H., Elias, S., & Ciechanover, A. (1983). Components of ubiquitin–protein ligase system. Resolution, affinity purification, and role in protein breakdown. The Journal of Biological Chemistry, 258, 8206–8214.PubMedGoogle Scholar
  7. 7.
    Wilk, S., & Orlowski, M. (1980). Cation-sensitive neutral endopeptidase: Isolation and specificity of the bovine pituitary enzyme. Journal of Neurochemistry, 35, 1172–1182.PubMedCrossRefGoogle Scholar
  8. 8.
    Wilk, S., & Orlowski, M. (1983). Evidence that pituitary cation-sensitive neutral endopeptidase is a multicatalytic protease complex. Journal of Neurochemistry, 40, 842–849.PubMedCrossRefGoogle Scholar
  9. 9.
    Orlowski, M., & Wilk, S. (1988). Multicatalytic proteinase complex’ or ‘multicatalytic proteinase’: A high-Mr-endopeptidase. The Biochemical Journal, 255, 751–751.PubMedCentralGoogle Scholar
  10. 10.
    Rieder, R., Ibrahim, A., & Etlinger, J. (1985). A particle-associated ATP-dependent proteolytic activity in erythroleukemia cells. The Journal of Biological Chemistry, 260, 2015–2018.PubMedGoogle Scholar
  11. 11.
    Waxman, L., Fagan, J., & Goldberg, A. L. (1987). Demonstration of two distinct high molecular weight proteases in rabbit reticulocytes, one of which degrades ubiquitin conjugates. The Journal of Biological Chemistry, 262, 2451–2457.PubMedGoogle Scholar
  12. 12.
    Azaryan, A., Banay-Schwartz, M., & Lajtha, A. (1989). ATP+ubiquitin-dependent proteinase and multicatalytic proteinase complex in bovine brain. Neurochemical Research, 14, 995–1001.PubMedCrossRefGoogle Scholar
  13. 13.
    Ikai, A., Nishigai, M., Tanaka, K., & Ichihara, A. (1991). Electron microscopy of 26 S complex containing 20 S proteasome. FEBS Letters, 292, 21–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Lowe, J., Stock, D., Jap, B., Zwickl, P., Baumeister, W., & Huber, R. (1995). Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 a resolution. Science, 268, 533–539.PubMedCrossRefGoogle Scholar
  15. 15.
    Walz, J., Erdmann, A., Kania, M., Typke, D., Koster, A. J., & Baumeister, W. (1998). 26S proteasome structure revealed by three-dimensional electron microscopy. Journal of Structural Biology, 121, 19–29.PubMedCrossRefGoogle Scholar
  16. 16.
    Nickell, S., Beck, F., Korinek, A., Mihalache, O., Baumeister, W., & Plitzko, J. M. (2007). Automated cryoelectron microscopy of “single particles” applied to the 26S proteasome. FEBS Letters, 581, 2751–2756.PubMedCrossRefGoogle Scholar
  17. 17.
    Groll, M., Ditzel, L., Lowe, J., Stock, D., Bochtler, M., Bartunik, H. D., & Huber, R. (1997). Structure of 20S proteasome from yeast at 2.4 a resolution. Nature, 386, 463–471.PubMedCrossRefGoogle Scholar
  18. 18.
    Sprangers, R., & Kay, L. E. (2007). Quantitative dynamics and binding studies of the 20S proteasome by NMR. Nature, 445, 618–622.PubMedCrossRefGoogle Scholar
  19. 19.
    Rosenzweig, R., Osmulski, P. A., Gaczynska, M., & Glickman, M. H. (2008). The central unit within the 19S regulatory particle of the proteasome. Nature Structural & Molecular Biology, 15, 573–580.CrossRefGoogle Scholar
  20. 20.
    Hershko, A., & Ciechanover, A. (1998). The ubiquitin system. Annual Review of Biochemistry, 67, 425–479.PubMedCrossRefGoogle Scholar
  21. 21.
    Saeki, Y., & Tanaka, K. (2007). Unlocking the proteasome door. Molecular Cell, 27, 865–867.PubMedCrossRefGoogle Scholar
  22. 22.
    Liu, C. W., Li, X., Thompson, D., Wooding, K., Chang, T. L., Tang, Z., Yu, H., Thomas, P. J., & DeMartino, G. N. (2006). ATP binding and ATP hydrolysis play distinct roles in the function of 26S proteasome. Molecular Cell, 24, 39–50.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Verma, R., Chen, S., Feldman, R., Schieltz, D., Yates, J., Dohmen, J., & Deshaies, R. J. (2000). Proteasomal proteomics: Identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity- purified proteasomes. Molecular Biology of the Cell, 11, 3425–3439.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Guerrero, C., Tagwerker, C., Kaiser, P., & Huang, L. (2006). An integrated mass spectrometry-based proteomic approach: Quantitative analysis of tandem affinity-purified in vivo cross-linked protein complexes (QTAX) to decipher the 26 S proteasome-interacting network. Molecular & Cellular Proteomics, 5, 366–378.CrossRefGoogle Scholar
  25. 25.
    Wang, X., Chen, C. F., Baker, P. R., Chen, P. L., Kaiser, P., & Huang, L. (2007). Mass spectrometric characterization of the affinity-purified human 26S proteasome complex. Biochemistry, 46, 3553–3565.PubMedCrossRefGoogle Scholar
  26. 26.
    Alsmadi, O., Muiya, P., Khalak, H., Al-Saud, H., Meyer, B. F., Al-Mohanna, F., Alshahid, M., & Dzimiri, N. (2009). Haplotypes encompassing the KIAA0391 and PSMA6 gene cluster confer a genetic link for myocardial infarction and coronary artery disease. Annals of Human Genetics, 73(5), 475–483.PubMedCrossRefGoogle Scholar
  27. 27.
    Sjakste, T., Kalis, M., Poudziunas, I., Pirags, V., Lazdins, M., Groop, L., & Sjakste, N. (2007). Association of microsatellite polymorphisms of the human 14q13.2 region with type 2 diabetes mellitus in Latvian and Finnish populations. Annals of Human Genetics, 71(6), 772–776.PubMedCrossRefGoogle Scholar
  28. 28.
    Sjakste, T., Eglite, J., Sochnevs, A., et al. (2004). Microsatellite genotyping of chromosome 14q13.2-14q13 in the vicinity of proteasomal gene PSMA6 and association with Graves’ disease in the Latvian population. Immunogenetics, 56(4), 238–243.PubMedCrossRefGoogle Scholar
  29. 29.
    Esseltine, D. L., & Mulligan, G. (2012). An historic perspective of proteasome inhibition. Seminars in Hematology, 49, 196–206.PubMedCrossRefGoogle Scholar
  30. 30.
    Hoeller, D., & Dikic, I. (2009). Targeting the ubiquitin system in cancer therapy. Nature, 458, 438–444.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of PhysiologyWayne State University School of MedicineDetroitUSA

Personalised recommendations