Editing Proteasome (section)

===20S core particle===
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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.