Degron Explained

A degron is a portion of a protein that is important in regulation of protein degradation rates. Known degrons include short amino acid sequences,[1] structural motifs and exposed amino acids (often lysine[2] or arginine[3]) located anywhere in the protein. In fact, some proteins can even contain multiple degrons.[4] Degrons are present in a variety of organisms, from the N-degrons (see N-end Rule) first characterized in yeast[5] to the PEST sequence of mouse ornithine decarboxylase.[6] Degrons have been identified in prokaryotes[7] as well as eukaryotes. While there are many types of different degrons, and a high degree of variability even within these groups, degrons are all similar for their involvement in regulating the rate of a protein's degradation.[8] [9] [10] Much like protein degradation (see proteolysis), mechanisms are categorized by their dependence or lack thereof on ubiquitin, a small protein involved in proteasomal protein degradation,[11] [12] [13] Degrons may also be referred to as “ubiquitin-dependent" or “ubiquitin-independent".

Types

Ubiquitin-dependent degrons are so named because they are implicated in the polyubiquitination process for targeting a protein to the proteasome.[14] [15] In some cases, the degron itself serves as the site for polyubiquitination as is seen in TAZ and β-catenin proteins.[16] Because the exact mechanism by which a degron is involved in a protein's polyubiqutination is not always known, degrons are classified as ubiquitin-dependent if their removal from the protein leads to less ubiquitination or if their addition to another protein leads to more ubiquitination.[17] [18]

In contrast, ubiquitin-independent degrons are not necessary for the polyubiquitination of their protein. For example, the degron on IκBα, a protein involved in the regulation of the immune system, was not shown to be involved in ubiquitination since its addition to green fluorescent protein (GFP) did not increase ubiquitination. However, a degron can only hint at the mechanism by which a protein is degraded[19] and so identifying and classifying a degron is only the first step in understanding the degradation process for its protein.

Identification

In order to identify a portion of a protein as a degron, there are often three steps performed. First, the degron candidate is fused to a stable protein, such as GFP, and protein abundances over time are compared between the unaltered protein and the fusion (as shown in green).[20] If the candidate is in fact a degron, then the abundance of the fusion protein will decrease much faster than that of the unaltered protein. Second, a mutant form of the degron's protein is designed such that it lacks the degron candidate. Similar to before, the abundance of the mutant protein over time is compared to that of the unaltered protein (as shown in red). If the deleted degron candidate is in fact a degron, then the mutant protein abundance will decrease much slower than that of the unaltered protein. Recall that degrons are often referred to as “ubiquitin-dependent” or “ubiquitin-independent” The third step performed is often done after one or both of the previous two steps, because it serves to identify the ubiquitin dependence or lack thereof of a previously identified degron. In this step, protein A and A’ (identical in every way except the presence of degron in A’) will be examined. Note that mutation or fusion procedures could be performed here, so either A is a protein like GFP and A’ is a fusion of GFP with the degron (as shown in green) or A’ is the degron's protein and A is a mutant form without the degron (as shown in Red.) The amount of ubiquitin bound to A and to A’ will be measured. A significant increase in the amount of ubiquitin in A’ as compared to A will suggest that the degron is ubiquitin-dependent.

See also

Notes and References

  1. Cho. Sungchan. Dreyfuss. Gideon. 2010-03-01. A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. Genes & Development. 24. 5. 438–442. 10.1101/gad.1884910. 1549-5477. 2827839. 20194437.
  2. Dohmen RJ, Wu P, Varshavsky A. Heat-inducible degron: a method for constructing temperature-sensitive mutants. Science. 1994. 263. 5151. 1273–1276. 10.1126/science.8122109. 8122109.
  3. Varshavsky. A.. 1996-10-29. The N-end rule: functions, mysteries, uses. Proceedings of the National Academy of Sciences. en. 93. 22. 12142–12149. 0027-8424. 37957. 8901547. 10.1073/pnas.93.22.12142. 1996PNAS...9312142V. free.
  4. Kanarek. Naama. London. Nir. Schueler-Furman. Ora. Ben-Neriah. Yinon. 2010-02-01. Ubiquitination and degradation of the inhibitors of NF-kappaB. Cold Spring Harbor Perspectives in Biology. 2. 2. a000166. 10.1101/cshperspect.a000166. 1943-0264. 2828279. 20182612.
  5. Bachmair. A.. Finley. D.. Varshavsky. A.. 1986-10-10. In vivo half-life of a protein is a function of its amino-terminal residue. Science. en. 234. 4773. 179–186. 10.1126/science.3018930. 0036-8075. 3018930. 1986Sci...234..179B.
  6. Loetscher. P.. Pratt. G.. Rechsteiner. M.. 1991-06-15. The C terminus of mouse ornithine decarboxylase confers rapid degradation on dihydrofolate reductase. Support for the pest hypothesis. The Journal of Biological Chemistry. 266. 17. 11213–11220. 10.1016/S0021-9258(18)99150-7. 0021-9258. 2040628. free.
  7. Burns. Kristin E.. Liu. Wei-Ting. Boshoff. Helena I. M.. Dorrestein. Pieter C.. Barry. Clifton E.. 2009-01-30. Proteasomal Protein Degradation in Mycobacteria Is Dependent upon a Prokaryotic Ubiquitin-like Protein. Journal of Biological Chemistry. en. 284. 5. 3069–3075. 10.1074/jbc.M808032200. 0021-9258. 2631945. 19028679. free.
  8. Ravid. Tommer. Hochstrasser. Mark. 2008-09-01. Degradation signal diversity in the ubiquitin-proteasome system. Nature Reviews. Molecular Cell Biology. 9. 9. 679–690. 10.1038/nrm2468. 1471-0072. 2606094. 18698327.
  9. Erales. Jenny. Coffino. Philip. 2014-01-01. Ubiquitin-independent proteasomal degradation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. Ubiquitin-Proteasome System. 1843. 1. 216–221. 10.1016/j.bbamcr.2013.05.008. 3770795. 23684952.
  10. Jariel-Encontre. Isabelle. Bossis. Guillaume. Piechaczyk. Marc. 2008-12-01. Ubiquitin-independent degradation of proteins by the proteasome. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1786. 2. 153–177. 10.1016/j.bbcan.2008.05.004. 0006-3002. 18558098.
  11. Asher. Gad. Tsvetkov. Peter. Kahana. Chaim. Shaul. Yosef. 2005-02-01. A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73. Genes & Development. en. 19. 3. 316–321. 10.1101/gad.319905. 0890-9369. 546509. 15687255.
  12. Erales. Jenny. Coffino. Philip. 2014-01-01. Ubiquitin-independent proteasomal degradation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1843. 1. 216–221. 10.1016/j.bbamcr.2013.05.008. 0006-3002. 3770795. 23684952.
  13. Hochstrasser. M.. 1996-01-01. Ubiquitin-dependent protein degradation. Annual Review of Genetics. 30. 405–439. 10.1146/annurev.genet.30.1.405. 0066-4197. 8982460.
  14. Coux. O.. Tanaka. K.. Goldberg. A. L.. 1996-01-01. Structure and functions of the 20S and 26S proteasomes. Annual Review of Biochemistry. 65. 801–847. 10.1146/annurev.bi.65.070196.004101. 0066-4154. 8811196.
  15. Lecker. Stewart H.. Goldberg. Alfred L.. Mitch. William E.. 2006-07-01. Protein Degradation by the Ubiquitin–Proteasome Pathway in Normal and Disease States. Journal of the American Society of Nephrology. en. 17. 7. 1807–1819. 10.1681/ASN.2006010083. 1046-6673. 16738015. free.
  16. Melvin. Adam T.. Woss. Gregery S.. Park. Jessica H.. Dumberger. Lukas D.. Waters. Marcey L.. Allbritton. Nancy L.. A Comparative Analysis of the Ubiquitination Kinetics of Multiple Degrons to Identify an Ideal Targeting Sequence for a Proteasome Reporter. PLOS ONE. 8. 10. e78082. 10.1371/journal.pone.0078082. 3812159. 24205101. 2013. 2013PLoSO...878082M. free.
  17. Wang. YongQiang. Guan. Shenheng. Acharya. Poulomi. Koop. Dennis R.. Liu. Yi. Liao. Mingxiang. Burlingame. Alma L.. Correia. Maria Almira. 2011-03-18. Ubiquitin-dependent proteasomal degradation of human liver cytochrome P450 2E1: identification of sites targeted for phosphorylation and ubiquitination. The Journal of Biological Chemistry. 286. 11. 9443–9456. 10.1074/jbc.M110.176685. 1083-351X. 3058980. 21209460. free.
  18. Ju. Donghong. Xie. Youming. 2006-04-21. Identification of the Preferential Ubiquitination Site and Ubiquitin-dependent Degradation Signal of Rpn4. Journal of Biological Chemistry. en. 281. 16. 10657–10662. 10.1074/jbc.M513790200. 0021-9258. 16492666. free.
  19. Schrader. Erin K. Harstad. Kristine G. Matouschek. Andreas. 2009-11-01. Targeting proteins for degradation. Nature Chemical Biology. 5. 11. 815–822. 10.1038/nchembio.250. 1552-4450. 4228941. 19841631.
  20. Li. Xianqiang. Zhao. Xiaoning. Fang. Yu. Jiang. Xin. Duong. Tommy. Fan. Connie. Huang. Chiao-Chain. Kain. Steven R.. 1998-12-25. Generation of Destabilized Green Fluorescent Protein as a Transcription Reporter. Journal of Biological Chemistry. en. 273. 52. 34970–34975. 10.1074/jbc.273.52.34970. 0021-9258. 9857028. free.

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