Editing Proteasome (section)

===Proteolysis===
{{See also|Threonine protease#mechanism}}
The proteasome functions as an [[endoprotease]].<ref>{{cite journal | vauthors = Seemüller E, Lupas A, Stock D, Löwe J, Huber R, Baumeister W | title = Proteasome from Thermoplasma acidophilum: a threonine protease | journal = Science | volume = 268 | issue = 5210 | pages = 579–82 | date = April 1995 | pmid = 7725107 | doi = 10.1126/science.7725107 | bibcode = 1995Sci...268..579S }}</ref><ref>{{cite journal | vauthors = Coux O, Tanaka K, Goldberg AL | title = Structure and functions of the 20S and 26S proteasomes | journal = Annual Review of Biochemistry | volume = 65 | pages = 801–47 | date = 1996 | pmid = 8811196 | doi = 10.1146/annurev.bi.65.070196.004101 }}</ref><ref>{{cite journal | vauthors = Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R | title = Structure of 20S proteasome from yeast at 2.4 A resolution | journal = Nature | volume = 386 | issue = 6624 | pages = 463–71 | date = April 1997 | pmid = 9087403 | doi = 10.1038/386463a0 | bibcode = 1997Natur.386..463G | s2cid = 4261663 }}</ref><ref>{{cite journal | vauthors = Dick TP, Nussbaum AK, Deeg M, Heinemeyer W, Groll M, Schirle M, Keilholz W, Stevanović S, Wolf DH, Huber R, Rammensee HG, Schild H | title = Contribution of proteasomal beta-subunits to the cleavage of peptide substrates analyzed with yeast mutants | journal = The Journal of Biological Chemistry | volume = 273 | issue = 40 | pages = 25637–46 | date = October 1998 | pmid = 9748229 | doi = 10.1074/jbc.273.40.25637 | doi-access = free }}</ref> The mechanism of proteolysis by the β subunits of the 20S core particle is through a threonine-dependent [[nucleophile|nucleophilic attack]]. This mechanism may depend on an associated [[water]] molecule for deprotonation of the reactive threonine [[hydroxyl]]. Degradation occurs within the central chamber formed by the association of the two β rings and normally does not release partially degraded products, instead reducing the substrate to short polypeptides typically 7–9 residues long, though they can range from 4 to 25 residues, depending on the organism and substrate. The biochemical mechanism that determines product length is not fully characterized.<ref name=Voges>{{cite journal | vauthors = Voges D, Zwickl P, Baumeister W | title = The 26S proteasome: a molecular machine designed for controlled proteolysis | journal = Annual Review of Biochemistry | volume = 68 | issue = 1 | pages = 1015–68 | year = 1999 | pmid = 10872471 | doi = 10.1146/annurev.biochem.68.1.1015 }}</ref> Although the three catalytic β subunits have a common mechanism, they have slightly different substrate specificities, which are considered chymotrypsin-like, trypsin-like, and peptidyl-glutamyl peptide-hydrolyzing (PHGH)-like. These variations in specificity are the result of interatomic contacts with local residues near the active sites of each subunit. Each catalytic β subunit also possesses a conserved lysine residue required for proteolysis.<ref name=Heinemeyer/>

Although the proteasome normally produces very short peptide fragments, in some cases these products are themselves biologically active and functional molecules. Certain [[transcription factor]]s regulating the expression of specific genes, including one component of the mammalian complex [[NF-κB]], are synthesized as inactive precursors whose ubiquitination and subsequent proteasomal degradation converts them to an active form. Such activity requires the proteasome to cleave the substrate protein internally, rather than processively degrading it from one terminus. It has been suggested that long [[loop (biochemistry)|loops]] on these proteins' surfaces serve as the proteasomal substrates and enter the central cavity, while the majority of the protein remains outside.<ref name=Rape>{{cite journal | vauthors = Rape M, Jentsch S | title = Taking a bite: proteasomal protein processing | journal = Nature Cell Biology | volume = 4 | issue = 5 | pages = E113–6 | date = May 2002 | pmid = 11988749 | doi = 10.1038/ncb0502-e113 | s2cid = 7126477 }}</ref> Similar effects have been observed in yeast proteins; this mechanism of selective degradation is known as ''regulated ubiquitin/proteasome dependent processing'' (RUP).<ref name=Rape2>{{cite journal | vauthors = Rape M, Jentsch S | title = Productive RUPture: activation of transcription factors by proteasomal processing | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1695 | issue = 1–3 | pages = 209–13 | date = November 2004 | pmid = 15571816 | doi = 10.1016/j.bbamcr.2004.09.022 | doi-access = free }}</ref>