Editing Proteasome (section)

== Discovery ==
Before the discovery of the ubiquitin–proteasome system, protein degradation in cells was thought to rely mainly on [[lysosome]]s, membrane-bound [[organelle]]s with [[acid]]ic and [[protease]]-filled interiors that can degrade and then recycle exogenous proteins and aged or damaged organelles.<ref name="Lodish" /> However, work by Joseph Etlinger and [[Alfred L. Goldberg]] in 1977 on ATP-dependent protein degradation in [[reticulocyte]]s, which lack lysosomes, suggested the presence of a second intracellular degradation mechanism.<ref>{{cite journal |author= Etlinger JD, Goldberg AL |title= A soluble ATP-dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 1 | pages = 54–8 | date = January 1977 | pmid = 264694 | pmc = 393195 | doi = 10.1073/pnas.74.1.54 |bibcode= 1977PNAS...74...54E |doi-access= free }}</ref> This was shown in 1978 to be composed of several distinct protein chains, a novelty among proteases at the time.<!--not a typo: it was published under this spelling--><ref name="Ciehanover">{{cite journal | vauthors = Ciehanover A, Hod Y, Hershko A | title = A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes | journal = Biochemical and Biophysical Research Communications | volume = 81 | issue = 4 | pages = 1100–5 | date = April 1978 | pmid = 666810 | doi = 10.1016/0006-291X(78)91249-4 }}</ref> Later work on modification of [[histone]]s led to the identification of an unexpected [[covalent]] modification of the histone protein by a bond between a [[lysine]] side chain of the histone and the [[C-terminus|C-terminal]] [[glycine]] residue of [[ubiquitin]], a protein that had no known function.<ref name="Goldknopf">{{cite journal | vauthors = Goldknopf IL, Busch H | title = Isopeptide linkage between nonhistone and histone 2A polypeptides of chromosomal conjugate-protein A24 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 3 | pages = 864–8 | date = March 1977 | pmid = 265581 | pmc = 430507 | doi = 10.1073/pnas.74.3.864 | bibcode = 1977PNAS...74..864G | doi-access = free }}</ref> It was then discovered that a previously identified protein associated with proteolytic degradation, known as ATP-dependent proteolysis factor 1 (APF-1), was the same protein as ubiquitin.<ref name="Ciechanover">{{cite journal | vauthors = Ciechanover A | title = Early work on the ubiquitin proteasome system, an interview with Aaron Ciechanover. Interview by CDD | journal = Cell Death and Differentiation | volume = 12 | issue = 9 | pages = 1167–77 | date = September 2005 | pmid = 16094393 | doi = 10.1038/sj.cdd.4401691 | doi-access = free }}</ref> The proteolytic activities of this system were isolated as a multi-protein complex originally called the multi-catalytic proteinase complex by Sherwin Wilk and Marion Orlowski.<ref name="Wilk">{{cite journal |vauthors= Wilk S, Orlowski M | title = Cation-sensitive neutral endopeptidase: isolation and specificity of the bovine pituitary enzyme |journal= Journal of Neurochemistry |volume=35 |issue =5 |pages= 1172–82 |date= November 1980 |pmid = 6778972 |doi= 10.1111/j.1471-4159.1980.tb07873.x | s2cid = 9028201 }}</ref> Later, the [[Adenosine triphosphate|ATP]]-dependent proteolytic complex that was responsible for ubiquitin-dependent protein degradation was discovered and was called the 26S proteasome.<ref>{{cite journal |vauthors= Arrigo AP, Tanaka, K, Goldberg F, Welch WJ |title= Identity of 19S prosome particle with the large multifunctional protease complex of mammalian cells. |journal=Nature |volume= 331 |issue= 6152 |pages= 192–94 |date= 1988 |doi=10.1038/331192a0|pmid= 3277060 |s2cid= 97688 }}{{cite journal |vauthors= Tanaka K, Waxman L, Goldberg AL |title= ATP serves two distinct roles in protein degradation in reticulocytes, one requiring and one independent of ubiquitin |journal= The Journal of Cell Biology |volume=96 |issue=6 |pages= 1580–5 |date= June 1983 |pmid= 6304111 |pmc= 2112434 |doi= 10.1083/jcb.96.6.1580 }}</ref><ref>{{cite journal |vauthors= Hough R, Pratt G, Rechsteiner M |title= Purification of two high molecular weight proteases from rabbit reticulocyte lysate |journal = The Journal of Biological Chemistry |volume= 262 |issue = 17 |pages= 8303–13 |date= June 1987 |doi= 10.1016/S0021-9258(18)47564-3 |pmid= 3298229 |doi-access= free }}</ref>

Much of the early work leading up to the discovery of the ubiquitin proteasome system occurred in the late 1970s and early 1980s at the [[Technion]] in the laboratory of [[Avram Hershko]], where [[Aaron Ciechanover]] worked as a graduate student. Hershko's year-long sabbatical in the laboratory of [[Irwin Rose]] at the [[Fox Chase Cancer Center]] provided key conceptual insights, though Rose later downplayed his role in the discovery.<ref name=Hershko>{{cite journal | vauthors = Hershko A | title = Early work on the ubiquitin proteasome system, an interview with Avram Hershko. Interview by CDD | journal = Cell Death and Differentiation | volume = 12 | issue = 9 | pages = 1158–61 | date = September 2005 | pmid = 16094391 | doi = 10.1038/sj.cdd.4401709 | doi-access = free }}</ref> The three shared the 2004 [[Nobel Prize in Chemistry]] for their work in discovering this system.<ref name=Nobel/>

Although [[electron microscopy]] (EM) data revealing the stacked-ring structure of the proteasome became available in the mid-1980s,<ref name=Kopp>{{cite journal | vauthors = Kopp F, Steiner R, Dahlmann B, Kuehn L, Reinauer H | title = Size and shape of the multicatalytic proteinase from rat skeletal muscle | journal = Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology | volume = 872 | issue = 3 | pages = 253–60 | date = August 1986 | pmid = 3524688 | doi = 10.1016/0167-4838(86)90278-5 }}</ref> the first structure of the proteasome core particle was not solved by [[X-ray crystallography]] until 1994.<ref name=Lowe>{{cite journal | vauthors = Löwe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R | title = Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution | journal = Science | volume = 268 | issue = 5210 | pages = 533–9 | date = April 1995 | pmid = 7725097 | doi = 10.1126/science.7725097 | bibcode = 1995Sci...268..533L }}</ref> Groundbreaking work on cryo-EM by [[Wolfgang Baumeister]]'s group revealed the overall architecture of the 26S proteasome <ref name="Schweitzer" /><ref name="Lander" /><ref name="Lasker" /><ref name="Sledz">{{cite journal |vauthors=Śledź P, Unverdorben P, Beck F, Pfeifer G, Schweitzer A, Förster F, Baumeister W |date=April 2013 |title=Structure of the 26S proteasome with ATP-γS bound provides insights into the mechanism of nucleotide-dependent substrate translocation |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=110 |issue=18 |pages=7264–7269 |bibcode=2013PNAS..110.7264S |doi=10.1073/pnas.1305782110 |pmc=3645540 |pmid=23589842 |doi-access=free}}</ref> and enabled biochemical experiments to provide a general mechanism for ubiquitin dependent degradation.<ref name=":8" /> In 2018, the first structure of the yeast 26S proteasome<ref name="Substrate-engaged 26 S proteasome s">{{cite journal |last1=de la Peña |first1=Andres H. |last2=Goodall |first2=Ellen A. |last3=Gates |first3=Stephanie N. |last4=Lander |first4=Gabriel C. |last5=Martin |first5=Andreas |title=Substrate-engaged 26 S proteasome structures reveal mechanisms for ATP-hydrolysis–driven translocation |journal=Science |date=30 November 2018 |volume=362 |issue=6418 |doi=10.1126/science.aav0725|pmid=30309908 |pmc=6519459 |bibcode=2018Sci...362..725D }}</ref> followed by the first atomic structures of the human 26S proteasome [[holoenzyme]]<ref name="Dong">{{cite journal |vauthors=Dong Y, Zhang S, Wu Z, Li X, Wang WL, Zhu Y, Stoilova-McPhie S, Lu Y, Finley D, Mao Y |date=November 2018 |title=Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome |journal=Nature |volume=565 |issue=7737 |pages=49–55 |doi=10.1038/s41586-018-0736-4 |pmc=6370054 |pmid=30479383|bibcode=2019Natur.565...49D }}</ref> in complex with a polyubiquitylated protein substrate were solved by [[cryogenic electron microscopy]], confirming the mechanisms by which the substrate is recognized, deubiquitylated, unfolded and degraded by the 26S proteasome. Detailed biochemistry has provided a general mechanism for ubiquitin-dependent degradation by the proteasome: binding of a substrate to the proteasome, engagement of an unstructured region to the AAA motor accompanied by a major conformational change of the proteasome, translocation dependent de-ubiquitination by Rpn11, followed by unfolding and proteolysis by the 20S core particle.<ref name=":8">{{cite journal |last1=Bard |first1=JAM |last2=Bashore |first2=C |last3=Dong |first3=KC |last4=Martin |first4=A |title=The 26S Proteasome Utilizes a Kinetic Gateway to Prioritize Substrate Degradation. |journal=Cell |date=4 April 2019 |volume=177 |issue=2 |pages=286–298.e15 |doi=10.1016/j.cell.2019.02.031 |pmid=30929903|pmc=6519451 }}</ref>

Cryo-[[Electron tomography]] (Cryo-ET) has also provided unique insight into proteasomes within cells. Looking at neurons, proteasomes were found to be in the same ground-state and processing states as determined by cryo-EM. Interestingly, most proteasomes were in the ground state suggesting that they were ready to start working when a cell undergoes proteotoxic stress.<ref>{{cite journal |last1=Asano |first1=Shoh |last2=Fukuda |first2=Yoshiyuki |last3=Beck |first3=Florian |last4=Aufderheide |first4=Antje |last5=Förster |first5=Friedrich |last6=Danev |first6=Radostin |last7=Baumeister |first7=Wolfgang |title=A molecular census of 26 S proteasomes in intact neurons |journal=Science |date=23 January 2015 |volume=347 |issue=6220 |pages=439–442 |doi=10.1126/science.1261197|pmid=25613890 |bibcode=2015Sci...347..439A }}</ref> In a separate study, when protein aggregates in the form of poly-Gly-Ala repeats are overexpressed, proteasome are captured stalled on these aggregates.<ref>{{cite journal |last1=Guo |first1=Qiang |last2=Lehmer |first2=Carina |last3=Martínez-Sánchez |first3=Antonio |last4=Rudack |first4=Till |last5=Beck |first5=Florian |last6=Hartmann |first6=Hannelore |last7=Pérez-Berlanga |first7=Manuela |last8=Frottin |first8=Frédéric |last9=Hipp |first9=Mark S. |last10=Hartl |first10=F. Ulrich |last11=Edbauer |first11=Dieter |last12=Baumeister |first12=Wolfgang |last13=Fernández-Busnadiego |first13=Rubén |title=In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment |journal=Cell |date=8 February 2018 |volume=172 |issue=4 |pages=696–705.e12 |doi=10.1016/j.cell.2017.12.030|pmid=29398115 |pmc=6035389 }}</ref> Cryo-ET of green algae [[Chlamydomonas reinhardtii]] found that 26S proteasomes within the nucleus cluster around the [[Nuclear pore complex]] and are specifically attached to the membrane.