degron
{{Short description|Part of a protein regulating rates of degradation}}
File:Ikba degron.jpg, an inhibitor of NF-κB and regulator of the immune system. The red region highlights the sixth ankyrin repeat domain, which contains a ubiquitin-independent degron.{{Cite journal|last1 = Fortmann|first1 = Karen T.|last2 = Lewis|first2 = Russell D.|last3 = Ngo|first3 = Kim A.|last4 = Fagerlund|first4 = Riku|last5 = Hoffmann|first5 = Alexander|date = 2015-08-28|title = A Regulated, Ubiquitin-Independent Degron in IκBα|journal = Journal of Molecular Biology|volume = 427|issue = 17|pages = 2748–2756|doi = 10.1016/j.jmb.2015.07.008|issn = 1089-8638|pmc = 4685248|pmid = 26191773}}]]
A degron is a portion of a protein that is important in regulation of protein degradation rates. Known degrons include short amino acid sequences,{{Cite journal|last1 = Cho|first1 = Sungchan|last2 = Dreyfuss|first2 = Gideon|date = 2010-03-01|title = A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity|journal = Genes & Development|volume = 24|issue = 5|pages = 438–442|doi = 10.1101/gad.1884910|issn = 1549-5477|pmc = 2827839|pmid = 20194437}} structural motifs and exposed amino acids (often lysine{{cite journal|vauthors=Dohmen RJ, Wu P, Varshavsky A|title=Heat-inducible degron: a method for constructing temperature-sensitive mutants|journal=Science|year=1994|volume=263|issue=5151|pages=1273–1276|doi=10.1126/science.8122109|pmid=8122109}} or arginine{{Cite journal|last = Varshavsky|first = A.|date = 1996-10-29|title = The N-end rule: functions, mysteries, uses|journal = Proceedings of the National Academy of Sciences|language = en|volume = 93|issue = 22|pages = 12142–12149|issn = 0027-8424|pmc = 37957|pmid = 8901547|doi=10.1073/pnas.93.22.12142|bibcode = 1996PNAS...9312142V|doi-access = free}}) located anywhere in the protein. In fact, some proteins can even contain multiple degrons.{{Cite journal|last1 = Kanarek|first1 = Naama|last2 = London|first2 = Nir|last3 = Schueler-Furman|first3 = Ora|last4 = Ben-Neriah|first4 = Yinon|date = 2010-02-01|title = Ubiquitination and degradation of the inhibitors of NF-kappaB|journal = Cold Spring Harbor Perspectives in Biology|volume = 2|issue = 2|pages = a000166|doi = 10.1101/cshperspect.a000166|issn = 1943-0264|pmc = 2828279|pmid = 20182612}} Degrons are present in a variety of organisms, from the N-degrons (see N-end Rule) first characterized in yeast{{Cite journal|last1 = Bachmair|first1 = A.|last2 = Finley|first2 = D.|last3 = Varshavsky|first3 = A.|date = 1986-10-10|title = In vivo half-life of a protein is a function of its amino-terminal residue|journal = Science|language = en|volume = 234|issue = 4773|pages = 179–186|doi = 10.1126/science.3018930|issn = 0036-8075|pmid = 3018930|bibcode = 1986Sci...234..179B}} to the PEST sequence of mouse ornithine decarboxylase.{{Cite journal|last1 = Loetscher|first1 = P.|last2 = Pratt|first2 = G.|last3 = Rechsteiner|first3 = M.|date = 1991-06-15|title = The C terminus of mouse ornithine decarboxylase confers rapid degradation on dihydrofolate reductase. Support for the pest hypothesis|journal = The Journal of Biological Chemistry|volume = 266|issue = 17|pages = 11213–11220|doi = 10.1016/S0021-9258(18)99150-7|issn = 0021-9258|pmid = 2040628|doi-access = free}} Degrons have been identified in prokaryotes{{Cite journal|last1 = Burns|first1 = Kristin E.|last2 = Liu|first2 = Wei-Ting|last3 = Boshoff|first3 = Helena I. M.|last4 = Dorrestein|first4 = Pieter C.|last5 = Barry|first5 = Clifton E.|date = 2009-01-30|title = Proteasomal Protein Degradation in Mycobacteria Is Dependent upon a Prokaryotic Ubiquitin-like Protein|journal = Journal of Biological Chemistry|language = en|volume = 284|issue = 5|pages = 3069–3075|doi = 10.1074/jbc.M808032200|issn = 0021-9258|pmc = 2631945|pmid = 19028679|doi-access = free}} 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.{{Cite journal|last1 = Ravid|first1 = Tommer|last2 = Hochstrasser|first2 = Mark|date = 2008-09-01|title = Degradation signal diversity in the ubiquitin-proteasome system|journal = Nature Reviews. Molecular Cell Biology|volume = 9|issue = 9|pages = 679–690|doi = 10.1038/nrm2468|issn = 1471-0072|pmc = 2606094|pmid = 18698327}}{{Cite journal|last1 = Erales|first1 = Jenny|last2 = Coffino|first2 = Philip|date = 2014-01-01|title = Ubiquitin-independent proteasomal degradation|journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|series = Ubiquitin-Proteasome System|volume = 1843|issue = 1|pages = 216–221|doi = 10.1016/j.bbamcr.2013.05.008|pmc = 3770795|pmid = 23684952}}{{Cite journal|last1 = Jariel-Encontre|first1 = Isabelle|last2 = Bossis|first2 = Guillaume|last3 = Piechaczyk|first3 = Marc|date = 2008-12-01|title = Ubiquitin-independent degradation of proteins by the proteasome|journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer|volume = 1786|issue = 2|pages = 153–177|doi = 10.1016/j.bbcan.2008.05.004|issn = 0006-3002|pmid = 18558098}} 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,{{Cite journal|last1 = Asher|first1 = Gad|last2 = Tsvetkov|first2 = Peter|last3 = Kahana|first3 = Chaim|last4 = Shaul|first4 = Yosef|date = 2005-02-01|title = A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73|journal = Genes & Development|language = en|volume = 19|issue = 3|pages = 316–321|doi = 10.1101/gad.319905|issn = 0890-9369|pmc = 546509|pmid = 15687255}}{{Cite journal|last1 = Erales|first1 = Jenny|last2 = Coffino|first2 = Philip|date = 2014-01-01|title = Ubiquitin-independent proteasomal degradation|journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|volume = 1843|issue = 1|pages = 216–221|doi = 10.1016/j.bbamcr.2013.05.008|issn = 0006-3002|pmc = 3770795|pmid = 23684952}}{{Cite journal|last = Hochstrasser|first = M.|date = 1996-01-01|title = Ubiquitin-dependent protein degradation|journal = Annual Review of Genetics|volume = 30|pages = 405–439|doi = 10.1146/annurev.genet.30.1.405|issn = 0066-4197|pmid = 8982460}} degrons may also be referred to as either “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.{{Cite journal|last1 = Coux|first1 = O.|last2 = Tanaka|first2 = K.|last3 = Goldberg|first3 = A. L.|date = 1996-01-01|title = Structure and functions of the 20S and 26S proteasomes|journal = Annual Review of Biochemistry|volume = 65|pages = 801–847|doi = 10.1146/annurev.bi.65.070196.004101|issn = 0066-4154|pmid = 8811196}}{{Cite journal|last1 = Lecker|first1 = Stewart H.|last2 = Goldberg|first2 = Alfred L.|last3 = Mitch|first3 = William E.|date = 2006-07-01|title = Protein Degradation by the Ubiquitin–Proteasome Pathway in Normal and Disease States|url = http://jasn.asnjournals.org/content/17/7/1807|journal = Journal of the American Society of Nephrology|language = en|volume = 17|issue = 7|pages = 1807–1819|doi = 10.1681/ASN.2006010083|issn = 1046-6673|pmid = 16738015|doi-access = free}} In some cases, the degron itself serves as the site for polyubiquitination as is seen in TAZ and β-catenin proteins.{{Cite journal|last1 = Melvin|first1 = Adam T.|last2 = Woss|first2 = Gregery S.|last3 = Park|first3 = Jessica H.|last4 = Dumberger|first4 = Lukas D.|last5 = Waters|first5 = Marcey L.|last6 = Allbritton|first6 = Nancy L.|title = A Comparative Analysis of the Ubiquitination Kinetics of Multiple Degrons to Identify an Ideal Targeting Sequence for a Proteasome Reporter|journal = PLOS ONE|volume = 8|issue = 10|pages = e78082|doi = 10.1371/journal.pone.0078082|pmc = 3812159|pmid = 24205101|year = 2013|bibcode = 2013PLoSO...878082M|doi-access = free}} 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.{{Cite journal|last1=Wang|first1=YongQiang|last2=Guan|first2=Shenheng|last3=Acharya|first3=Poulomi|last4=Koop|first4=Dennis R.|last5=Liu|first5=Yi|last6=Liao|first6=Mingxiang|last7=Burlingame|first7=Alma L.|last8=Correia|first8=Maria Almira|date=2011-03-18|title=Ubiquitin-dependent proteasomal degradation of human liver cytochrome P450 2E1: identification of sites targeted for phosphorylation and ubiquitination|journal=The Journal of Biological Chemistry|volume=286|issue=11|pages=9443–9456|doi=10.1074/jbc.M110.176685|issn=1083-351X|pmc=3058980|pmid=21209460|doi-access=free}}{{Cite journal|last1=Ju|first1=Donghong|last2=Xie|first2=Youming|date=2006-04-21|title=Identification of the Preferential Ubiquitination Site and Ubiquitin-dependent Degradation Signal of Rpn4|journal=Journal of Biological Chemistry|language=en|volume=281|issue=16|pages=10657–10662|doi=10.1074/jbc.M513790200|issn=0021-9258|pmid=16492666|doi-access=free}}
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{{Cite journal|last1=Schrader|first1=Erin K|last2=Harstad|first2=Kristine G|last3=Matouschek|first3=Andreas|date=2009-11-01|title=Targeting proteins for degradation|journal=Nature Chemical Biology|volume=5|issue=11|pages=815–822|doi=10.1038/nchembio.250|issn=1552-4450|pmc=4228941|pmid=19841631}} 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).{{Cite journal|last1=Li|first1=Xianqiang|last2=Zhao|first2=Xiaoning|last3=Fang|first3=Yu|last4=Jiang|first4=Xin|last5=Duong|first5=Tommy|last6=Fan|first6=Connie|last7=Huang|first7=Chiao-Chain|last8=Kain|first8=Steven R.|date=1998-12-25|title=Generation of Destabilized Green Fluorescent Protein as a Transcription Reporter|journal=Journal of Biological Chemistry|language=en|volume=273|issue=52|pages=34970–34975|doi=10.1074/jbc.273.52.34970|issn=0021-9258|pmid=9857028|doi-access=free}} 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.
References
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