Degradation of proteins on proteasomes

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Degradation of defective proteins[edit | edit source]

Proteasomes also degrade defective proteins that the cell failed to synthesize correctly (about 30% of all native proteins in the cell) and whose elimination takes place immediately during translation or shortly after it[1]. If newly synthesized defective proteins are located in the endoplasmic reticulum (ER) – mainly proteins misfolded into tertiary structures – they are subject to a process in which proteasomes cooperate with the ER and which is called ERAD (endoplasmic reticulum-associated degradation). During ERAD, the misfolded protein is first marked with a specific code (these are glycans), then it is transported across the ER membrane into cytosol and degraded by nearby proteasomes[2]. In the case of non-native proteins that are poorly folded and aggregated, they are taken up in cytosol using two compartments called JUNQ (juxta-nuclear quality control) and IPOD (insoluble protein deposit). Even these proteins are finally degraded in proteasomes[3]. However, proteasomes do not only degrade defective proteins, but also significantly participate in the processing of functional proteins in the sense of influencing their function. Degradation of a protein can be an important part of various signaling events in the cell, as we will see below.

Nuclear and cytoplasmatic proteasomes[edit | edit source]

Proteasomes are contained in the cytoplasm and the nucleus, where they move freely and quickly. On the other hand, the transfer of proteasomes from the cytoplasm, where there are more of them, to the nucleus (it cannot go in the other direction) is slow. During mitosis, the two separate populations of proteasomes, nuclear and cytoplasmic, can fuse and intermingle[4]. The total amount of proteasomes in a cell is in the hundreds to thousands of nanograms per milligram of all cellular proteins, although it can be significantly greater in cancer cells than in healthy cells[5]. Further details on the localization of proteasomes in the cytoplasm and nucleus can be found in the literature[6].

The ubiquitin-proteasome system[edit | edit source]

Degradation of proteins using proteasomes is a very sophisticated process that takes place within the framework of the so-called ubiquitin-proteasome system (UPS) or the so-called ubiquitin-proteasome pathway. An important role in this process is played by the small (76 amino acids, 8.5 kDa) protein ubiquitin, which was discovered already in 1975, without its function being known. However, the name already implies that this protein is abundantly found in all eukaryotic cells (it is "ubiquitous" i.e. "occurring everywhere"). Today we already know that ubiquitin serves to mark proteins in a process called ubiquitination or ubiquitinylation of a protein. The importance, diversity and complex context of protein labeling with ubiquitin today reaches the level of the most important post-translational modification of proteins, which is phosphorylation[7].

Ubiquitination processes[edit | edit source]

  1. Ubiquitin is first bound (activated) in the cell when ATP is consumed by the so-called ubiquitin-activating enzyme E1.
  2. It is subsequently transferred to the ubiquitin-transferring (or ubiquitin-conjugating) enzyme E2.
  3. Further transfer of ubiquitin to the protein to be degraded (hereafter PDG; or to the forming chain of ubiquitins to PDG) is conditioned by E3 ubiquitin ligase, which can specifically recognize proteins to be degraded.

In other words, the E1 and E2 enzymes mainly serve only to transport ubiquitins, while the E3 enzymes handle their final attachment to PDG, recognized by these enzymes. First, the first ubiquitin is bound to the PDG, then the second, the second, the third, etc. The fact that E3 enzymes specifically recognize different PDGs also means that there are few different E1s in cells (according to [8], there are at least two E1s in human cells enzymes, namely Uba6 and Ube1) and E2 enzymes, while E3 enzymes exist in diverse numbers (hundreds) for different groups of proteins destined for degradation.

Ubiquitin-ligases[edit | edit source]

We recognize two basic genera of ubiquitin ligases, which differ in the presence of an active domain: either they contain a HECT (homologous to E6-Associated Protein C-Terminus) domain, or a RING (really interesting new gene) domain[9]-[10]. Moreover, in addition to the classic E1-E2-E3 cascade, we now also know the so-called E4 enzymes, which can participate in the extension of the polyubiquitin chain[11].

Mode of attachment of ubiquitins[edit | edit source]

A key question is also how the ubiquitins are connected to each other in the chain. Not every polyubiquitin chain is prima facie the kiss of death. The most common way of linking two ubiquitins in a polyubiquitin chain is via lysine 48 (so-called K48 chain) or lysine 63 (so-called K63 chain), however, there are also ubiquitin chains linked via lysine 6, 11, 27, 29 or 33, in some exceptions, these chains can even be branched[12]. Today we cannot say exactly what the meaning of the whole variety of these signals is. K48 chains in particular are considered to be the "kiss of death", while K63 chains mainly play other roles in cell signaling. However, it has recently been shown that also proteins marked with K63 chains can be recognized by proteasomes and degraded in them[13]. There is even the possibility that K63 chains can be converted directly on the tagged protein to K48 chains[14].

Deubiquitination[edit | edit source]

In the eukaryotic cell, in addition to ubiquitination of proteins, their deubiquitination also occurs. The enzymes responsible for this process are called deubiquitinases and are denoted by the abbreviation DUB. We can divide them into the following five groups:

  1. ubiquitin C-terminal hydrolases,
  2. ubiquitin specific proteases,
  3. proteases with the Machado-Joseph disease domain,
  4. proteases from ovarian tumors,
  5. proteases with a JAMM domain[15].

Today, 75 DUBs are known, which interact with hundreds of proteins and play an immense number of different roles in the eukaryotic cell[16]. Note that one of the JAMM domain deubiquitinases, referred to in human cells as Poh1, is part of the eukaryotic proteasome and plays a key role in its proper functioning.

Proteasome[edit | edit source]

Characteristics[edit | edit source]

A protein that carries a K48 polyubiquitin chain. It can be recognized by the so-called 26S proteasome and degraded in it.

The 26S proteasome is a common type of proteasome found in our cells. It consists of two basic parts[17]:

  1. 20S proteasome, i.e. the core particle, which has the shape of a cylinder and in which the proteolysis of PDG itself takes place;
  2. 19S proteasome or regulatory particle, which is also called PA700.

Core particle[edit | edit source]

The 20S proteasome consists of a total of four rings. The two outer ones are made up of seven α units and the two inner ones are made up of seven β subunits. The active protein-cleaving sites are in the β rings and face the inside of the 20S proteasome cylinder, namely:

  • β1 subunit with caspase-like activity;
  • β2 subunit with trypsin-like activity;
  • β5 subunit with chymotrypsin-like activity..

In addition to the normal 20S proteasome, inducible proteasomes also exist in our cells. These have other active sites (β1i, β2i and β5i), which are called immunoproteasomes or mixed proteasomes. They play a role in the immune response of cells to foreign substances[18]. A very special type of proteasome exists in the thymus, the so-called thymoproteasome. They contain a β5t subunit with unusual catalytic activity. Their role is related to the positive selection of CD8+ T cells[19].

Regulatory particle[edit | edit source]

Regulatory particles bind to the outer, i.e. α ring of the 20S proteasome. In addition to the 19S proteasome, these can also be other complexes, such as PA28 or PA200, or even proteins that reversibly attach to the 20S proteasome in substoichiometric amounts[20]. Although the organization of proteasomes varies dynamically, it has been shown that the 26S proteasome remains intact during protein degradation[21].

Proteasome

The 26S proteasome regulatory particle (PA700) contains two basic, interconnected regions: a base and a lid. In the base we can find six different AAA+ ATPases and another four subunits. Its main mission is to regulate entry into the interior of the 20S proteasome[22]. The lid contains nine non-ATPase subunits[23] and its primary function is the deubiquitination of ubiquitinated proteins by the JAMM domain DUB Poh1 before their entry into the interior of 26S proteasomes[24].

Degradation of non-ubiquitinated proteins[edit | edit source]

A typical protein, degraded in a eukaryotic cell by the proteasome, must be ubiquitinated. However, according to recent findings, about 20% of all proteins cleaved by proteasomes in eukaryotic cells may not have ubiquitin labeling. Such proteins contain disordered sites in their structures that serve as a non-specific signal for degradation in proteasomes without the need for ubiquitination of the given protein[25].

The role of the proteasome in antigen presentation:
A – Protein
B – Proteasome
C – MHC I protein synthesis
D – Peptides to be presented
E – ER
F – Plasmatic membrane
1. Ubiquitination
2. Degradation of protein into peptides by the proteasome
3. Peptide transport into the ER lumen by ABC transporters
4. Binding of peptides in the notch of the MHC I complex
5. Antigen presentation on the plasma membrane

Degradation of ubiquitinated proteins[edit | edit source]

We will focus on the mechanism of degradation of ubiquitinated PDGs in 26S proteasomes.

Some subunits from the base (ubiquitin receptors) and also some proteins that only transiently associate with 26S proteasomes play a key role in the recognition of the ubiquitinated protein[26]. If the ubiquitinated protein is already bound to the 26S proteasome, its polyubiquitin chain can be variously cleaved by the proteasome and resynthesized by deubiquitinases and ubiquitin ligases[27]. It has also been shown that the reduction in the intensity of degradation of ubiquitins themselves in the proteasome is related to the activity of a specific DUB, called Ubp6, which is not a constant subunit of the 26S proteasome[28].

Steps of the degradation[edit | edit source]

  • Before PDG degradation itself, the polyubiquitin chain is usually cleaved en bloc (as a whole, at once) by Poh1 and further removed by other DUBs[29].
  • The unraveling of the protein into the primary structure and its movement into the opening of the proteasome is then connected with the hydrolysis of ATP by AAA+ ATPases[30].
  • The unfolded protein can be "stored" in the α rings if the β rings are still occupied by the degradation of the previous PDG[31]. Proteins can enter the 20S proteasome from both sides[32]. Degradation takes place until the resulting oligopeptides are small enough to spontaneously diffuse out[33].
  • As soon as the oligopeptides get out of the 26S proteasomes, they are further cleaved in the cell by other peptidases to amino acids that can be used for further proteosynthesis[34], or are used within the immune system as antigens[35].

Regulation of protein activity[edit | edit source]

Some proteins are not completely degraded by 26S proteasomes, but are actually activated. This happens by degrading other proteins that are bound to them and inhibit them. A typical example is the activation of the so-called nuclear factor-κB (NF-κB), which normally occurs in the cytoplasm in a complex with its inhibitor I-κB. Once the I-κB is ubiquitinated and degraded, NF-κB translocates to the nucleus and triggers the transcription of the relevant genes[36]. The function of 26S proteasomes is not only connected with the regulation of the amount of a given protein in the cell, but also with the regulation of the activity of various proteins. It follows that the UPS plays a key role in many therapeutically important processes, such as inflammatory diseases, neurodegenerative processes, muscular dystrophies, viral infections or carcinogenesis[37]-[38].

Proteasome inhibitors[edit | edit source]

Proteasome inhibition leads to apoptosis of some tumor cells. Although the exact mechanism of their action on cells is not yet known, they are used as antitumor drugs. The most prominent representative is bortezomib, which is used to treat multiple myeloma.

Links[edit | edit source]

Related articles[edit | edit source]

Taken from[edit | edit source]


Reference[edit | edit source]

  1. ↑ SCHUBERT, U – ANTÓN, L C – GIBBS, J. , et al. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature [online]. 2000, vol. 404, no. 6779, p. 770-4, Available from <https://www.ncbi.nlm.nih.gov/pubmed/10783891>. ISSN 0028-0836. 
  2. ↑ HIRSCH, Christian – GAUSS, Robert – HORN, Sabine C. , et al. The ubiquitylation machinery of the endoplasmic reticulum. Nature [online]. 2009, vol. 458, no. 7237, p. 453-60, Available from <https://www.ncbi.nlm.nih.gov/pubmed/19325625>. ISSN 0028-0836 (print), 1476-4687. 
  3. ↑ KAGANOVICH, Daniel – KOPITO, Ron – FRYDMAN, Judith. Misfolded proteins partition between two distinct quality control compartments. Nature [online]. 2008, vol. 454, no. 7208, p. 1088-95, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746971/?tool=pubmed>. ISSN 0028-0836 (print), 1476-4687. 
  4. ↑ REITS, E A – BENHAM, A M – PLOUGASTEL, B. , et al. Dynamics of proteasome distribution in living cells. EMBO J [online]. 1997, vol. 16, no. 20, p. 6087-94, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1326292/?tool=pubmed>. ISSN 0261-4189. 
  5. ↑ KUMATORI, A – TANAKA, K – INAMURA, N. , et al. Abnormally high expression of proteasomes in human leukemic cells. Proc Natl Acad Sci U S A [online]. 1990, vol. 87, no. 18, p. 7071-5, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC54685/?tool=pubmed>. ISSN 0027-8424. 
  6. ↑ WÓJCIK, Cezary – DEMARTINO, George N. Intracellular localization of proteasomes. Int J Biochem Cell Biol [online]. 2003, vol. 35, no. 5, p. 579-89, Available from <https://www.ncbi.nlm.nih.gov/pubmed/12672451>. ISSN 1357-2725. 
  7. ↑ KOMANDER, David. The emerging complexity of protein ubiquitination. Biochem Soc Trans [online]. 2009, vol. 37, no. Pt 5, p. 937-53, Available from <https://www.ncbi.nlm.nih.gov/pubmed/19754430>. ISSN 0300-5127 (print), 1470-8752. 
  8. ↑ JIN, Jianping – LI, Xue – GYGI, Steven P. , et al. Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature [online]. 2007, vol. 447, no. 7148, p. 1135-8, Available from <https://www.ncbi.nlm.nih.gov/pubmed/17597759>. ISSN 0028-0836 (print), 1476-4687. 
  9. ↑ ROTIN, Daniela – KUMAR, Sharad. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol [online]. 2009, vol. 10, no. 6, p. 398-409, Available from <https://www.ncbi.nlm.nih.gov/pubmed/19436320>. ISSN 1471-0072 (print), 1471-0080. 
  10. ↑ DESHAIES, Raymond J – JOAZEIRO, Claudio A P. RING domain E3 ubiquitin ligases. Annu Rev Biochem [online]. 2009, vol. 78, p. 399-434, Available from <https://www.ncbi.nlm.nih.gov/pubmed/19489725>. ISSN 0066-4154 (print), 1545-4509. 
  11. ↑ HOPPE, Thorsten. Multiubiquitylation by E4 enzymes: 'one size' doesn't fit all. Trends Biochem Sci [online]. 2005, vol. 30, no. 4, p. 183-7, Available from <https://www.ncbi.nlm.nih.gov/pubmed/15817394>. ISSN 0968-0004. 
  12. ↑ IKEDA, Fumiyo – DIKIC, Ivan. Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series. EMBO Rep [online]. 2008, vol. 9, no. 6, p. 536-42, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427391/?tool=pubmed>. ISSN 1469-221X (print), 1469-3178. 
  13. ↑ SAEKI, Yasushi – KUDO, Tai – SONE, Takayuki. , et al. Lysine 63-linked polyubiquitin chain may serve as a targeting signal for the 26S proteasome. EMBO J [online]. 2009, vol. 28, no. 4, p. 359-71, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646160/?tool=pubmed>. ISSN 0261-4189 (print), 1460-2075. 
  14. ↑ NEWTON, Kim – MATSUMOTO, Marissa L – WERTZ, Ingrid E. , et al. Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies. Cell [online]. 2008, vol. 134, no. 4, p. 668-78, Available from <https://www.ncbi.nlm.nih.gov/pubmed/18724939>. ISSN 0092-8674 (print), 1097-4172. 
  15. ↑ KOMANDER, David – CLAGUE, Michael J – URBÉ, Sylvie. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol [online]. 2009, vol. 10, no. 8, p. 550-63, Available from <https://www.ncbi.nlm.nih.gov/pubmed/19626045>. ISSN 1471-0072 (print), 1471-0080. 
  16. ↑ SOWA, Mathew E – BENNETT, Eric J – GYGI, Steven P. , et al. Defining the human deubiquitinating enzyme interaction landscape. Cell [online]. 2009, vol. 138, no. 2, p. 389-403, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716422/?tool=pubmed>. ISSN 0092-8674 (print), 1097-4172. 
  17. ↑ BEDFORD, Lynn – PAINE, Simon – SHEPPARD, Paul W. , et al. Assembly, structure, and function of the 26S proteasome. Trends Cell Biol [online]. 2010, vol. 20, no. 7, p. 391-401, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902798/?tool=pubmed>. ISSN 0962-8924 (print), 1879-3088. 
  18. ↑ STREHL, Britta – SEIFERT, Ulrike – KRÜGER, Elke. , et al. Interferon-gamma, the functional plasticity of the ubiquitin-proteasome system, and MHC class I antigen processing. Immunol Rev [online]. 2005, vol. 207, p. 19-30, Available from <https://www.ncbi.nlm.nih.gov/pubmed/16181324>. ISSN 0105-2896. 
  19. ↑ MURATA, Shigeo – TAKAHAMA, Yousuke – TANAKA, Keiji. Thymoproteasome: probable role in generating positively selecting peptides. Curr Opin Immunol [online]. 2008, vol. 20, no. 2, p. 192-6, Available from <https://www.ncbi.nlm.nih.gov/pubmed/18403190>. ISSN 0952-7915. 
  20. ↑ DEMARTINO, George N – GILLETTE, Thomas G. Proteasomes: machines for all reasons. Cell [online]. 2007, vol. 129, no. 4, p. 659-62, Available from <https://www.ncbi.nlm.nih.gov/pubmed/17512401>. ISSN 0092-8674. 
  21. ↑ KRIEGENBURG, Franziska – SEEGER, Michael – SAEKI, Yasushi. , et al. Mammalian 26S proteasomes remain intact during protein degradation. Cell [online]. 2008, vol. 135, no. 2, p. 355-65, Available from <https://www.ncbi.nlm.nih.gov/pubmed/18957208>. ISSN 0092-8674 (print), 1097-4172. 
  22. ↑ LI, Xiaohua – DEMARTINO, George N. Variably modulated gating of the 26S proteasome by ATP and polyubiquitin. Biochem J [online]. 2009, vol. 421, no. 3, p. 397-404, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872633/?tool=pubmed>. ISSN 0264-6021 (print), 1470-8728. 
  23. ↑ SHARON, Michal – TAVERNER, Thomas – AMBROGGIO, Xavier I. , et al. Structural organization of the 19S proteasome lid: insights from MS of intact complexes. PLoS Biol [online]. 2006, vol. 4, no. 8, p. e267, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1523230/?tool=pubmed>. ISSN 1544-9173 (print), 1545-7885. 
  24. ↑ VERMA, Rati – ARAVIND, L – OANIA, Robert. , et al. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science [online]. 2002, vol. 298, no. 5593, p. 611-5, Available from <https://www.ncbi.nlm.nih.gov/pubmed/12183636>. ISSN 0036-8075 (print), 1095-9203. 
  25. ↑ BAUGH, James M – VIKTOROVA, Ekaterina G – PILIPENKO, Evgeny V. Proteasomes can degrade a significant proportion of cellular proteins independent of ubiquitination. J Mol Biol [online]. 2009, vol. 386, no. 3, p. 814-27, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649715/?tool=pubmed>. ISSN 0022-2836 (print), 1089-8638. 
  26. ↑ VERMA, Rati – OANIA, Robert – GRAUMANN, Johannes. , et al. Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system. Cell [online]. 2004, vol. 118, no. 1, p. 99-110, Available from <https://www.ncbi.nlm.nih.gov/pubmed/15242647>. ISSN 0092-8674. 
  27. ↑ CROSAS, Bernat – HANNA, John – KIRKPATRICK, Donald S. , et al. Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell [online]. 2006, vol. 127, no. 7, p. 1401-13, Available from <https://www.ncbi.nlm.nih.gov/pubmed/17190603>. ISSN 0092-8674. 
  28. ↑ HANNA, John – MEIDES, Alice – ZHANG, Dan Phoebe. , et al. A ubiquitin stress response induces altered proteasome composition. Cell [online]. 2007, vol. 129, no. 4, p. 747-59, Available from <https://www.ncbi.nlm.nih.gov/pubmed/17512408>. ISSN 0092-8674. 
  29. ↑ KOULICH, Elena – LI, Xiaohua – DEMARTINO, George N. Relative structural and functional roles of multiple deubiquitylating proteins associated with mammalian 26S proteasome. Mol Biol Cell [online]. 2008, vol. 19, no. 3, p. 1072-82, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2262970/?tool=pubmed>. ISSN 1059-1524 (print), 1939-4586. 
  30. ↑ STRIEBEL, Frank – KRESS, Wolfgang – WEBER-BAN, Eilika. Controlled destruction: AAA+ ATPases in protein degradation from bacteria to eukaryotes. Curr Opin Struct Biol [online]. 2009, vol. 19, no. 2, p. 209-17, Available from <https://www.ncbi.nlm.nih.gov/pubmed/19362814>. ISSN 0959-440X (print), 1879-033X. 
  31. ↑ SHARON, Michal – WITT, Susanne – FELDERER, Karin. , et al. 20S proteasomes have the potential to keep substrates in store for continual degradation. J Biol Chem [online]. 2006, vol. 281, no. 14, p. 9569-75, Available from <https://www.ncbi.nlm.nih.gov/pubmed/16446364>. ISSN 0021-9258. 
  32. ↑ HUTSCHENREITER, Silke – TINAZLI, Ali – MODEL, Kirstin. , et al. Two-substrate association with the 20S proteasome at single-molecule level. EMBO J [online]. 2004, vol. 23, no. 13, p. 2488-97, Available from <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC449772/?tool=pubmed>. ISSN 0261-4189. 
  33. ↑ KÖHLER, A – CASCIO, P – LEGGETT, D S. , et al. The axial channel of the proteasome core particle is gated by the Rpt2 ATPase and controls both substrate entry and product release. Mol Cell [online]. 2001, vol. 7, no. 6, p. 1143-52, Available from <https://www.ncbi.nlm.nih.gov/pubmed/11430818>. ISSN 1097-2765. 
  34. ↑ VABULAS, Ramunas M – HARTL, F Ulrich. Protein synthesis upon acute nutrient restriction relies on proteasome function. Science [online]. 2005, vol. 310, no. 5756, p. 1960-3, Available from <https://www.ncbi.nlm.nih.gov/pubmed/16373576>. ISSN 0036-8075 (print), 1095-9203. 
  35. ↑ KLOETZEL, Peter M. Generation of major histocompatibility complex class I antigens: functional interplay between proteasomes and TPPII. Nat Immunol [online]. 2004, vol. 5, no. 7, p. 661-9, Available from <https://www.ncbi.nlm.nih.gov/pubmed/15224091>. ISSN 1529-2908. 
  36. ↑ RAPE, Michael – JENTSCH, Stefan. Productive RUPture: activation of transcription factors by proteasomal processing. Biochim Biophys Acta [online]. 2004, vol. 1695, no. 1-3, p. 209-13, Available from <https://www.ncbi.nlm.nih.gov/pubmed/15571816>. ISSN 0006-3002. 
  37. ↑ RUBINSZTEIN, David C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature [online]. 2006, vol. 443, no. 7113, p. 780-6, Available from <https://www.ncbi.nlm.nih.gov/pubmed/17051204>. ISSN 0028-0836 (print), 1476-4687. 
  38. ↑ SCHWARTZ, Alan L – CIECHANOVER, Aaron. Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu Rev Pharmacol Toxicol [online]. 2009, vol. 49, p. 73-96, Available from <https://www.ncbi.nlm.nih.gov/pubmed/18834306>. ISSN 0362-1642. 
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