Editing Proteasome (section)

==Structure and organization==
[[File:1G0U subunits sideview.png|thumb|right|Schematic diagram of the proteasome 20S core particle viewed from one side. The α subunits that make up the outer two rings are shown in green, and the β subunits that make up the inner two rings are shown in blue.]]
The proteasome subcomponents are often referred to by their [[Svedberg]] sedimentation coefficient (denoted ''S''). The proteasome most exclusively used in mammals is the cytosolic 26S proteasome, which is about 2,000 [[atomic mass unit|kilodaltons]] (kDa) in [[molecular mass]] containing one 20S protein subcomplex and one 19S regulatory cap subcomplex. Doubly capped proteasomes are referred to as 30S proteasomes also exist in the cell. The 20S core is hollow and provides an enclosed cavity in which proteins are degraded; openings at the two ends of the core are gates that allow the target protein to enter. Each end of the core particle can associate with a 19S regulatory subunit that contains multiple [[ATPase]] [[active site]]s and ubiquitin binding sites; it is this structure that recognizes polyubiquitinated proteins and transfers them to the catalytic core.<ref>{{cite journal |last1=Bard |first1=Jared A. M. |last2=Goodall |first2=Ellen A. |last3=Greene |first3=Eric R. |last4=Jonsson |first4=Erik |last5=Dong |first5=Ken C. |last6=Martin |first6=Andreas |title=Structure and Function of the 26S Proteasome |journal=Annual Review of Biochemistry |date=June 2018 |volume=87 |pages=697–724 |doi=10.1146/annurev-biochem-062917-011931 |pmid=29652515 |pmc=6422034 }}</ref><ref>{{cite journal |last1=Greene |first1=Eric R |last2=Dong |first2=Ken C |last3=Martin |first3=Andreas |title=Understanding the 26S proteasome molecular machine from a structural and conformational dynamics perspective |journal=Current Opinion in Structural Biology |date=1 April 2020 |volume=61 |pages=33–41 |doi=10.1016/j.sbi.2019.10.004 |pmid=31783300 |pmc=7156321 }}</ref><ref>{{cite journal |last1=Arkinson |first1=Connor |last2=Dong |first2=Ken C. |last3=Gee |first3=Christine L. |last4=Martin |first4=Andreas |title=Mechanisms and regulation of substrate degradation by the 26S proteasome |journal=Nature Reviews Molecular Cell Biology |date=February 2025 |volume=26 |issue=2 |pages=104–122 |doi=10.1038/s41580-024-00778-0 |pmid=39362999 |pmc=11772106 |pmc-embargo-date=February 1, 2026 }}</ref>

Several alternative caps can also bind the 20S core: 11S (PA26) or Blm10 (PA200) are also known to associate with the core and can bind either one or both sides. An alternative form of regulatory subunit called the 11S particle can associate with the core in essentially the same manner as the 19S particle; the 11S may play a role in degradation of foreign peptides such as those produced after infection by a [[virus]].<ref name="Wang">{{cite journal | vauthors = Wang J, Maldonado MA | title = The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases | journal = Cellular & Molecular Immunology | volume = 3 | issue = 4 | pages = 255–61 | date = August 2006 | pmid = 16978533 }}</ref> Archaea and bacteria also have proteasomes and have alternative caps that bind their cores. The following will discuss the structure and function of these subcomplexes.

===20S core particle===
{{Redirect|20S|the decade|20s}}
The number and diversity of subunits contained in the 20S core particle depends on the organism; the number of distinct and specialized subunits is larger in multicellular than unicellular organisms and larger in eukaryotes than in prokaryotes. All 20S particles consist of four stacked heptameric ring structures that are themselves composed of two different types of subunits; α subunits are structural in nature, whereas β subunits are predominantly [[catalysis|catalytic]]. The α subunits are [[pseudoenzyme]]s homologous to β subunits. They are assembled with their N-termini adjacent to that of the β subunits.<ref name="pmid21211719"/> The outer two rings in the stack consist of seven α subunits each, which serve as docking domains for the regulatory particles and the alpha subunits N-termini ({{Pfam|PF10584}}) form a gate that blocks unregulated access of substrates to the interior cavity.<ref name=Smith07>{{cite journal | vauthors = Smith DM, Chang SC, Park S, Finley D, Cheng Y, Goldberg AL | title = Docking of the proteasomal ATPases' carboxyl termini in the 20S proteasome's alpha ring opens the gate for substrate entry | journal = Molecular Cell | volume = 27 | issue = 5 | pages = 731–44 | date = September 2007 | pmid = 17803938 | pmc = 2083707 | doi = 10.1016/j.molcel.2007.06.033 }}</ref> The inner two rings each consist of seven β subunits and in their N-termini contain the protease active sites that perform the proteolysis reactions.<ref name="MEROPS-T1">{{cite web |title=MEROPS Family T1 |url=https://www.ebi.ac.uk/merops/cgi-bin/famsum?family=T01 |publisher=EMBL-EBI |access-date=16 February 2019}}</ref> Three distinct catalytic activities were identified in the purified complex: chymotrypsin-like, trypsin-like and peptidylglutamyl-peptide hydrolyzing.<ref name=Wilk2>{{cite journal | vauthors = Wilk S, Orlowski M | title = Evidence that pituitary cation-sensitive neutral endopeptidase is a multicatalytic protease complex | journal = Journal of Neurochemistry | volume = 40 | issue = 3 | pages = 842–9 | date = March 1983 | pmid = 6338156 | doi = 10.1111/j.1471-4159.1983.tb08056.x | s2cid = 23508675 }}</ref> The size of the proteasome is relatively conserved and is about 150 [[angstrom]]s (Å) by 115&nbsp;Å. The interior chamber is at most 53&nbsp;Å wide, though the entrance can be as narrow as 13&nbsp;Å, suggesting that substrate proteins must be at least partially unfolded to enter.<ref name=Nandi>{{cite journal | vauthors = Nandi D, Tahiliani P, Kumar A, Chandu D | title = The ubiquitin-proteasome system | journal = Journal of Biosciences | volume = 31 | issue = 1 | pages = 137–55 | date = March 2006 | pmid = 16595883 | doi = 10.1007/BF02705243 | s2cid = 21603835 | url = http://eprints.iisc.ac.in/6416/1/The_ubiquitin-proteasome_system.pdf }}</ref>

In [[archaea]] such as ''[[Thermoplasma acidophilum]]'', all the α and all the β subunits are identical, whereas eukaryotic proteasomes such as those in [[yeast]] contain seven distinct types of each subunit. In [[mammal]]s, the β1, β2, and β5 subunits are catalytic; although they share a common mechanism, they have three distinct substrate specificities considered [[chymotrypsin]]-like, [[trypsin]]-like, and [[peptidyl-glutamyl peptide-hydrolyzing]] (PHGH).<ref name=Heinemeyer>{{cite journal | vauthors = Heinemeyer W, Fischer M, Krimmer T, Stachon U, Wolf DH | title = The active sites of the eukaryotic 20 S proteasome and their involvement in subunit precursor processing | journal = The Journal of Biological Chemistry | volume = 272 | issue = 40 | pages = 25200–9 | date = October 1997 | pmid = 9312134 | doi = 10.1074/jbc.272.40.25200 | doi-access = free }}</ref> Alternative β forms denoted β1i, β2i, and β5i can be expressed in [[hematopoietic]] cells in response to exposure to pro-[[Inflammation|inflammatory]] [[cell signaling|signal]]s such as [[cytokine]]s, in particular, [[interferon gamma]]. The proteasome assembled with these alternative subunits is known as the ''[[immunoproteasome]]'', whose substrate specificity is altered relative to the normal proteasome.<ref name=Nandi/>
Recently an alternative proteasome was identified in human cells that lack the α3 core subunit.<ref name="Padmanabhan A 2016">{{cite journal | vauthors = Padmanabhan A, Vuong SA, Hochstrasser M | title = Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells | journal = Cell Reports | volume = 14 | issue = 12 | pages = 2962–74 | date = March 2016 | pmid = 26997268 | doi = 10.1016/j.celrep.2016.02.068 | pmc=4828729}}</ref> These proteasomes (known as the α4-α4 proteasomes) instead form 20S core particles containing an additional α4 subunit in place of the missing α3 subunit. These alternative 'α4-α4' proteasomes have been known previously to exist in yeast.<ref>{{cite journal | vauthors = Velichutina I, Connerly PL, Arendt CS, Li X, Hochstrasser M | title = Plasticity in eucaryotic 20S proteasome ring assembly revealed by a subunit deletion in yeast | journal = The EMBO Journal | volume = 23 | issue = 3 | pages = 500–10 | date = February 2004 | pmid = 14739934 | doi = 10.1038/sj.emboj.7600059 | pmc=1271798}}</ref> Although the precise function of these proteasome isoforms is still largely unknown, cells expressing these proteasomes show enhanced resistance to toxicity induced by metallic ions such as cadmium.<ref name="Padmanabhan A 2016"/><ref>{{cite journal | vauthors = Kusmierczyk AR, Kunjappu MJ, Funakoshi M, Hochstrasser M | title = A multimeric assembly factor controls the formation of alternative 20S proteasomes | journal = Nature Structural & Molecular Biology | volume = 15 | issue = 3 | pages = 237–44 | date = March 2008 | pmid = 18278055 | doi = 10.1038/nsmb.1389 | s2cid = 21181637 }}</ref>

The peptides that are formed by the 20S core have recently been shown to act as important metabolites for both programmed cell death and for immunity.<ref name=":6">{{cite journal |title=Constitutive protein degradation induces acute cell death via proteolysis products |journal=bioRxiv |date=2023 |doi=10.1101/2023.02.06.527237 | vauthors = Chen S, Prakash S, Helgason E, Gilchrist CL, Kenner LR, Srinivasan R, Sterne-Weiler T, Hafner M, Piskol R, Dueber EC, Hamidi H, Endres N, Ye X, Fairbrother WJ, Wertz IE }}</ref><ref>{{cite journal |last1=Goldberg |first1=Karin |last2=Lobov |first2=Arseniy |last3=Antonello |first3=Paola |last4=Shmueli |first4=Merav D. |last5=Yakir |first5=Idan |last6=Weizman |first6=Tal |last7=Ulman |first7=Adi |last8=Sheban |first8=Daoud |last9=Laser |first9=Einav |last10=Kramer |first10=Matthias P. |last11=Shteinvil |first11=Ronen |last12=Chen |first12=Guoyun |last13=Ibraheem |first13=Angham |last14=Sysoeva |first14=Vera |last15=Fishbain-Yoskovitz |first15=Vered |date=March 2025 |title=Cell-autonomous innate immunity by proteasome-derived defence peptides |journal=Nature |volume=639 |issue=8056 |pages=1032–1041 |doi=10.1038/s41586-025-08615-w |last16=Mohapatra |first16=Gayatree |last17=Abramov |first17=Anat |last18=Shimshi |first18=Sandy |last19=Ogneva |first19=Kseniia |last20=Nandy |first20=Madhurima |last21=Amidror |first21=Sivan |last22=Bootz-Maoz |first22=Hadar |last23=Kuo |first23=Shanny H. |last24=Dezorella |first24=Nili |last25=Kacen |first25=Assaf |last26=Javitt |first26=Aaron |last27=Lau |first27=Gee W. |last28=Yissachar |first28=Nissan |last29=Hayouka |first29=Zvi |last30=Merbl |first30=Yifat|pmid=40044870 |pmc=11946893 |bibcode=2025Natur.639.1032G }}</ref>  [[Molecular glue]]s that target [[BRD4]] for degradation, lead to 26S proteasome generated peptides that release [[Inhibitor of apoptosis]] (IAPs) leading to [[Apoptosis]],<ref name=":6" /> suggesting that the peptides generated by the 26S act as secondary metabolites that drive major cell processes.

===19S regulatory particle===
The 19S particle in eukaryotes consists of 19 individual proteins and is divisible into two subassemblies, a 9-subunit base that binds directly to the α ring of the 20S core particle, and a 10-subunit lid. Six of the nine base proteins are ATPase subunits from the AAA Family, and an evolutionary homolog of these ATPases exists in archaea, called PAN (proteasome-activating nucleotidase).<ref>{{cite journal | vauthors = Zwickl P, Ng D, Woo KM, Klenk HP, Goldberg AL | title = An archaebacterial ATPase, homologous to ATPases in the eukaryotic 26 S proteasome, activates protein breakdown by 20 S proteasomes | journal = The Journal of Biological Chemistry | volume = 274 | issue = 37 | pages = 26008–14 | date = September 1999 | pmid = 10473546 | doi = 10.1074/jbc.274.37.26008 | doi-access = free }}</ref> The association of the 19S and 20S particles requires the binding of ATP to the 19S ATPase subunits, and ATP hydrolysis is required for the assembled complex to degrade folded and ubiquitinated proteins. Note that only the step of substrate unfolding requires energy from ATP hydrolysis, while ATP-binding alone can support all the other steps required for protein degradation (e.g., complex assembly, gate opening, translocation, and proteolysis).<ref name="Smith">{{cite journal | vauthors = Smith DM, Kafri G, Cheng Y, Ng D, Walz T, Goldberg AL | title = ATP binding to PAN or the 26S ATPases causes association with the 20S proteasome, gate opening, and translocation of unfolded proteins | journal = Molecular Cell | volume = 20 | issue = 5 | pages = 687–98 | date = December 2005 | pmid = 16337593 | doi = 10.1016/j.molcel.2005.10.019 | doi-access = free }}</ref><ref name="Liu"/> In fact, ATP binding to the ATPases by itself supports the rapid degradation of unfolded proteins. However, while ATP hydrolysis is required for unfolding only, it is not yet clear whether this energy may be used in the coupling of some of these steps.<ref name=Liu>{{cite journal | vauthors = Liu CW, Li X, Thompson D, Wooding K, Chang TL, Tang Z, Yu H, Thomas PJ, DeMartino GN | title = ATP binding and ATP hydrolysis play distinct roles in the function of 26S proteasome | journal = Molecular Cell | volume = 24 | issue = 1 | pages = 39–50 | date = October 2006 | pmid = 17018291 | doi = 10.1016/j.molcel.2006.08.025 | pmc = 3951175 }}</ref><ref>{{cite journal | vauthors = Lam YA, Lawson TG, Velayutham M, Zweier JL, Pickart CM | title = A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal | journal = Nature | volume = 416 | issue = 6882 | pages = 763–7 | date = April 2002 | pmid = 11961560 | doi = 10.1038/416763a | bibcode = 2002Natur.416..763L | s2cid = 4421764 }}</ref>

[[File:26S proteasome structure.jpg|thumb|right|Cartoon representation of the 26S proteasome.<ref name=Beck>{{cite journal | vauthors = Beck F, Unverdorben P, Bohn S, Schweitzer A, Pfeifer G, Sakata E, Nickell S, Plitzko JM, Villa E, Baumeister W, Förster F | title = Near-atomic resolution structural model of the yeast 26S proteasome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 37 | pages = 14870–5 | date = September 2012 | pmid = 22927375 | doi = 10.1073/pnas.1213333109 | pmc=3443124| bibcode = 2012PNAS..10914870B | doi-access = free }}</ref>]]

In 2012, two independent efforts have elucidated the molecular architecture of the 26S proteasome by [[single particle analysis|single particle electron microscopy]].<ref name=Lander>{{cite journal | vauthors = Lander GC, Estrin E, Matyskiela ME, Bashore C, Nogales E, Martin A | title = Complete subunit architecture of the proteasome regulatory particle | journal = Nature | volume = 482 | issue = 7384 | pages = 186–91 | date = February 2012 | pmid = 22237024 | pmc = 3285539| doi = 10.1038/nature10774 | bibcode = 2012Natur.482..186L }}</ref><ref name=Lasker>{{cite journal | vauthors = Lasker K, Förster F, Bohn S, Walzthoeni T, Villa E, Unverdorben P, Beck F, Aebersold R, Sali A, Baumeister W | title = Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 5 | pages = 1380–7 | date = January 2012 | pmid = 22307589 | doi = 10.1073/pnas.1120559109 | pmc=3277140| doi-access = free | bibcode = 2012PNAS..109.1380L }}</ref> In 2016, three independent efforts have determined the first near-atomic resolution structure of the human 26S proteasome in the absence of substrates by cryo-EM.<ref name=Chen>{{cite journal | vauthors = Chen S, Wu J, Lu Y, Ma YB, Lee BH, Yu Z, Ouyang Q, Finley DJ, Kirschner MW, Mao Y | title = Structural basis for dynamic regulation of the human 26S proteasome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 46 | pages = 12991–12996 | date = November 2016 | pmid = 27791164 | pmc = 5135334 | doi = 10.1073/pnas.1614614113 | bibcode = 2016PNAS..11312991C | doi-access = free }}</ref><ref name=Huang>{{cite journal | vauthors = Huang X, Luan B, Wu J, Shi Y | title = An atomic structure of the human 26S proteasome | journal = Nature Structural & Molecular Biology | volume = 23 | issue = 9 | pages = 778–785 | date = September 2016 | pmid = 27428775 | doi = 10.1038/nsmb.3273 | s2cid = 21909333 }}</ref><ref name=Schweitzer>{{cite journal | vauthors = Schweitzer A, Aufderheide A, Rudack T, Beck F, Pfeifer G, Plitzko JM, Sakata E, Schulten K, Förster F, Baumeister W | title = Structure of the human 26S proteasome at a resolution of 3.9 Å | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 28 | pages = 7816–7821 | date = July 2016 | pmid = 27791164 | pmc = 5135334 | doi = 10.1073/pnas.1614614113 | bibcode = 2016PNAS..11312991C | doi-access = free }}</ref>  In the heart of the 19S, directly adjacent to the 20S, are the AAA-ATPases ([[AAA proteins]]) that assemble to a heterohexameric ring of the order Rpt1/Rpt2/Rpt6/Rpt3/Rpt4/Rpt5. This ring is a trimer of dimers: Rpt1/Rpt2, Rpt6/Rpt3, and Rpt4/Rpt5 dimerize via their N-terminal coiled-coils. These coiled-coils protrude from the hexameric ring. The largest regulatory particle non-ATPases Rpn1 and Rpn2 bind to the tips of Rpt1/2 and Rpt6/3, respectively. The ubiquitin receptor Rpn13 binds to Rpn2 and completes the base sub-complex. The lid covers one half of the AAA-ATPase hexamer (Rpt6/Rpt3/Rpt4) and, unexpectedly, directly contacts the 20S via Rpn6 and to lesser extent Rpn5. The subunits Rpn9, Rpn5, Rpn6, Rpn7, Rpn3, and Rpn12, which are structurally related among themselves and to subunits of the [[COP9 signalosome|COP9 complex]] and [[Eukaryotic initiation factor 3|eIF3]] (hence called PCI subunits) assemble to a horseshoe-like structure enclosing the Rpn8/Rpn11 heterodimer. Rpn11, the [[deubiquitinating enzyme]], is placed at the mouth of the AAA-ATPase hexamer, ideally positioned to remove ubiquitin moieties immediately before translocation of substrates into the 20S. The second ubiquitin receptor identified to date, Rpn10, is positioned at the periphery of the lid, near subunits Rpn8 and Rpn9.

==== Conformational changes of 19S ====
These initial structures showed that the 19S RP adopted a number of states (termed s1, s2, s3, and s4 in yeast) which provided a model for how substrates were recruited and subsequently degraded by the proteasome.<ref name="Unverdorben">{{cite journal |vauthors=Unverdorben P, Beck F, Śledź P, Schweitzer A, Pfeifer G, Plitzko JM, Baumeister W, Förster F |date=April 2014 |title=Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=111 |issue=15 |pages=5544–9 |bibcode=2014PNAS..111.5544U |doi=10.1073/pnas.1403409111 |pmc=3992697 |pmid=24706844 |doi-access=free}}</ref><ref name="Matyskiela">{{cite journal |vauthors=Matyskiela ME, Lander GC, Martin A |date=July 2013 |title=Conformational switching of the 26S proteasome enables substrate degradation |journal=Nature Structural & Molecular Biology |volume=20 |issue=7 |pages=781–788 |doi=10.1038/nsmb.2616 |pmc=3712289 |pmid=23770819}}</ref>  A hallmark of the AAA-ATPase configuration in this predominant low-energy state is a staircase- or lockwasher-like arrangement of the AAA-domains.<ref name="Beck" /><ref name="Lander" />   These states could be manipulated upon the addition of ATPgS,<ref name="Sledz" /> substrate, or by the non-essential DUB Ubp6.  The s1 state was proposed to be the resting state of the proteasome, allowing for a protein substrate to engage the AAA motor.  Upon binding a substrate, the proteasome would shift to a processing state, in which a central channel from the top of the AAA motor into the 20S proteolytic chamber would form allowing a direct passage of a substrate from the 19S RP into the proteolytic site.   Subsequent studies with the human proteasome have shown many more sub-states, and provide a model for ATP dependent translocation of a substrate.<ref name="Zhuy">{{cite journal |vauthors=Zhu Y, Wang WL, Yu D, Ouyang Q, Lu Y, Mao Y |date=April 2018 |title=Structural mechanism for nucleotide-driven remodeling of the AAA-ATPase unfoldase in the activated human 26S proteasome |journal=Nature Communications |volume=9 |issue=1 |page=1360 |bibcode=2018NatCo...9.1360Z |doi=10.1038/s41467-018-03785-w |pmc=5893597 |pmid=29636472}}</ref><ref name="Chen" /><ref name="Dong" />

In 2018, the first structure of a processing proteasome bound to a substrate was solved using cryo-EM, confirming biochemistry that showed that de-ubiquitination by Rpn11 was performed in a translocation dependent manner <ref name=":0">{{cite journal |last1=Worden |first1=Evan J. |last2=Dong |first2=Ken C. |last3=Martin |first3=Andreas |title=An AAA Motor-Driven Mechanical Switch in Rpn11 Controls Deubiquitination at the 26S Proteasome |journal=Molecular Cell |date=September 2017 |volume=67 |issue=5 |pages=799–811.e8 |doi=10.1016/j.molcel.2017.07.023|pmid=28844860 }}</ref> and revealing key steps in translocation.<ref name="Substrate-engaged 26 S proteasome s"/>  Subsequently, a major effort has elucidated the detailed structures of deubiquitylation, initiation of translocation and processive unfolding of substrates by determining seven atomic structures of substrate-engaged 26S proteasome simultaneously.<ref name="Dong" />

[[File:3 conformational states of 26S proteasome.jpg|thumb|300px|Three distinct conformational states of the 26S proteasome.<ref name=Unverdorben/> The conformations are hypothesized to be responsible for recruitment of the substrate, its irreversible commitment, and finally processing and translocation into the core particle, where degradation occurs.]]

===Regulation of the 20S by the 19S===
The 19S regulatory particle is responsible for stimulating the 20S to degrade proteins. A primary function of the 19S regulatory ATPases is to open the gate in the 20S that blocks the entry of substrates into the degradation chamber.<ref>{{cite journal | vauthors = Köhler A, Cascio P, Leggett DS, Woo KM, Goldberg AL, Finley D | title = The axial channel of the proteasome core particle is gated by the Rpt2 ATPase and controls both substrate entry and product release | journal = Molecular Cell | volume = 7 | issue = 6 | pages = 1143–52 | date = June 2001 | pmid = 11430818 | doi = 10.1016/S1097-2765(01)00274-X | doi-access = free }}</ref> The mechanism by which the proteasomal ATPase open this gate has been recently elucidated.<ref name=Smith07/> 20S gate opening, and thus substrate degradation, requires the C-termini of the proteasomal ATPases, which contains a specific [[sequence motif|motif]] (i.e., HbYX motif). The ATPases C-termini bind into pockets in the top of the 20S, and tether the ATPase complex to the 20S proteolytic complex, thus joining the substrate unfolding equipment with the 20S degradation machinery. Binding of these C-termini into these 20S pockets by themselves stimulates opening of the gate in the 20S in much the same way that a "key-in-a-lock" opens a door.<ref name=Smith07/> The precise mechanism by which this "key-in-a-lock" mechanism functions has been structurally elucidated in the context of human 26S proteasome at near-atomic resolution, suggesting that the insertion of five C-termini of ATPase subunits Rpt1/2/3/5/6 into the 20S surface pockets are required to fully open the 20S gate, confirming work previously done on yeast proteasome.<ref name=Zhuy /><ref name=Dong /><ref name=Chen />

===Other regulatory particles===
{{Redirect-distinguish|11S|S11 (disambiguation){{!}}S11|11 (disambiguation){{!}}11 (plural)}}

==== 11S ====
20S proteasomes can also associate with a second type of regulatory particle, the 11S regulatory particle, a heptameric structure that does not contain any ATPases and can promote the degradation of short [[peptide]]s but not of complete proteins. It is presumed that this is because the complex cannot unfold larger substrates. This structure is also known as PA28, REG, or PA26.<ref name="pmid21211719">{{cite journal |last1=Stadtmueller |first1=BM |last2=Hill |first2=CP |title=Proteasome activators. |journal=Molecular Cell |date=7 January 2011 |volume=41 |issue=1 |pages=8–19 |doi=10.1016/j.molcel.2010.12.020 |pmid=21211719 |pmc=3040445}}</ref> The mechanisms by which it binds to the core particle through the C-terminal tails of its subunits and induces α-ring [[conformational change]]s to open the 20S gate suggest a similar mechanism for the 19S particle.<ref name=Forster>{{cite journal | vauthors = Förster A, Masters EI, Whitby FG, Robinson H, Hill CP | title = The 1.9 A structure of a proteasome-11S activator complex and implications for proteasome-PAN/PA700 interactions | journal = Molecular Cell | volume = 18 | issue = 5 | pages = 589–99 | date = May 2005 | pmid = 15916965 | doi = 10.1016/j.molcel.2005.04.016 | doi-access = free }}</ref> The expression of the 11S particle is induced by interferon gamma and is responsible, in conjunction with the immunoproteasome β subunits, for the generation of peptides that bind to the [[major histocompatibility complex]].<ref name=Wang/>

==== BLM10/PA200 ====
Yet another type of non-ATPase regulatory particle is the Blm10 (yeast) or PA200/[[PSME4]] (human). It opens only one α subunit in the 20S gate and itself folds into a dome with a very small pore over it.<ref name="pmid21211719"/>

==== Archaeal Proteasomes ====
[[Archaea]] also contain a proteasome degradation pathway with a 20S core and a regulatory particle consisting of the Proteasome-Activating Nucleotidase (PAN), that shares similarities to the 19S proteasome.  Like the eukaryotic 19S, PAN is a [[AAA-ATPase]], containing N-terminal coiled coils, an OB ring, an ATPase domain with an HBXY motif that interacts with the archaeal 20S.

==== Bacterial Proteasomes ====
Actinobacteria have acquired a proteasome degradation pathway, including its own 20S core particle and a [[AAA proteins|AAA protein]] motor, MPA (mycobacterial proteasome activator).  Unlike the base subcomplex of the 19S, MPA is a homohexameric motor complex, containing the ATPase sites, a tandem (oligosaccharide/oligonucleotide-binding) OB ring, and [[Coiled coil]]s that extend off N-termini off the OB ring.  The C-terminus contains HBXY motifs that contact the 20S core particle in a similar way as with other regulatory particles.  Targeting to MPA requires a prokaryotic protein, [[Prokaryotic ubiquitin-like protein]] (or Pup) that functions as ubiquitin as a tag that can be attached to a protein substrate, though the structure of Pup is unrelated to that of ubiquitin.  Once attached, a puplyated protein can be targeted to MPA through the coiled-coil and can be directed through the AAA motor into the 20S for degradation.<ref>{{cite journal |last1=Kavalchuk |first1=Mikhail |last2=Jomaa |first2=Ahmad |last3=Müller |first3=Andreas U. |last4=Weber-Ban |first4=Eilika |title=Structural basis of prokaryotic ubiquitin-like protein engagement and translocation by the mycobacterial Mpa-proteasome complex |journal=Nature Communications |date=12 January 2022 |volume=13 |issue=1 |page=276 |doi=10.1038/s41467-021-27787-3|pmid=35022401 |pmc=8755798 |bibcode=2022NatCo..13..276K }}</ref><ref>{{cite journal |last1=Striebel |first1=F |last2=Hunkeler |first2=M |last3=Summer |first3=H |last4=Weber-Ban |first4=E |title=The mycobacterial Mpa-proteasome unfolds and degrades pupylated substrates by engaging Pup's N-terminus. |journal=The EMBO Journal |date=7 April 2010 |volume=29 |issue=7 |pages=1262–71 |doi=10.1038/emboj.2010.23 |pmid=20203624|pmc=2857465 }}</ref>