1932

Abstract

As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic cells. The proteasome's cellular functions range from general protein homeostasis and stress response to the control of vital processes such as cell division and signal transduction. To reliably process all the proteins presented to it in the complex cellular environment, the proteasome must combine high promiscuity with exceptional substrate selectivity. Recent structural and biochemical studies have shed new light on the many steps involved in proteasomal substrate processing, including recognition, deubiquitination, and ATP-driven translocation and unfolding. In addition, these studies revealed a complex conformational landscape that ensures proper substrate selection before the proteasome commits to processive degradation. These advances in our understanding of the proteasome's intricate machinery set the stage for future studies on how the proteasome functions as a major regulator of the eukaryotic proteome.

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2018-06-20
2024-05-27
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Literature Cited

  1. 1.  Komander D, Rape M 2012. The ubiquitin code. Annu. Rev. Biochem. 81:203–29
    [Google Scholar]
  2. 2.  Bhattacharyya S, Yu H, Mim C, Matouschek A 2014. Regulated protein turnover: snapshots of the proteasome in action. Nat. Rev. Mol. Cell Biol. 15:122–33
    [Google Scholar]
  3. 3.  Collins GA, Goldberg AL 2017. The logic of the 26S proteasome. Cell 169:792–806
    [Google Scholar]
  4. 4.  Finley D. 2009. Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu. Rev. Biochem. 78:477–513
    [Google Scholar]
  5. 5.  Goldberg AL. 2007. Functions of the proteasome: from protein degradation and immune surveillance to cancer therapy. Biochem. Soc. Trans. 35:12–17
    [Google Scholar]
  6. 6.  Budenholzer L, Cheng CL, Li Y, Hochstrasser M 2017. Proteasome structure and assembly. J. Mol. Biol. 429:3500–24
    [Google Scholar]
  7. 7.  Sadre-Bazzaz K, Whitby FG, Robinson H, Formosa T, Hill CP 2010. Structure of a Blm10 complex reveals common mechanisms for proteasome binding and gate opening. Mol. Cell 37:728–35
    [Google Scholar]
  8. 8.  Tian G, Park S, Lee MJ, Huck B, McAllister F et al. 2011. An asymmetric interface between the regulatory and core particles of the proteasome. Nat. Struct. Mol. Biol. 18:1259–67
    [Google Scholar]
  9. 9.  Gillette TG, Kumar B, Thompson D, Slaughter CA, DeMartino GN 2008. Differential roles of the COOH termini of AAA subunits of PA700 (19 S regulator) in asymmetric assembly and activation of the 26 S proteasome. J. Biol. Chem. 283:31813–22
    [Google Scholar]
  10. 10.  Glickman MH, Rubin DM, Fried VA, Finley D 1998. The regulatory particle of the Saccharomyces cerevisiae proteasome. Mol. Cell. Biol. 18:3149–62
    [Google Scholar]
  11. 11.  Groll M, Bajorek M, Kohler A, Moroder L, Rubin DM et al. 2000. A gated channel into the proteasome core particle. Nat. Struct. Biol. 7:1062–67
    [Google Scholar]
  12. 12.  Rabl J, Smith DM, Yu Y, Chang SC, Goldberg AL, Cheng Y 2008. Mechanism of gate opening in the 20S proteasome by the proteasomal ATPases. Mol. Cell 30:360–68
    [Google Scholar]
  13. 13.  Smith DM, Chang SC, Park S, Finley D, Cheng Y, Goldberg AL 2007. Docking of the proteasomal ATPases’ carboxyl termini in the 20S proteasome's α ring opens the gate for substrate entry. Mol. Cell 27:731–44
    [Google Scholar]
  14. 14.  Finley D, Chen X, Walters KJ 2016. Gates, channels, and switches: elements of the proteasome machine. Trends Biochem. Sci. 41:77–93
    [Google Scholar]
  15. 15.  Glickman MH, Rubin DM, Coux O, Wefes I, Pfeifer G et al. 1998. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell 94:615–23
    [Google Scholar]
  16. 16.  Saeki Y, Tanaka K 2012. Assembly and function of the proteasome. Methods Mol. Biol. 832:315–37
    [Google Scholar]
  17. 17.  He J, Kulkarni K, da Fonseca PC, Krutauz D, Glickman MH et al. 2012. The structure of the 26S proteasome subunit Rpn2 reveals its PC repeat domain as a closed toroid of two concentric α-helical rings. Structure 20:513–21
    [Google Scholar]
  18. 18.  Shi Y, Chen X, Elsasser S, Stocks BB, Tian G et al. 2016. Rpn1 provides adjacent receptor sites for substrate binding and deubiquitination by the proteasome. Science 351:aad9421
    [Google Scholar]
  19. 19.  Husnjak K, Elsasser S, Zhang N, Chen X, Randles L et al. 2008. Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 453:481–88
    [Google Scholar]
  20. 20.  van Nocker S, Sadis S, Rubin DM, Glickman M, Fu H et al. 1996. The multiubiquitin-chain-binding protein Mcb1 is a component of the 26S proteasome in Saccharomyces cerevisiae and plays a nonessential, substrate-specific role in protein turnover. Mol. Cell. Biol. 16:6020–28
    [Google Scholar]
  21. 21.  Deveraux Q, Ustrell V, Pickart C, Rechsteiner M 1994. A 26 S protease subunit that binds ubiquitin conjugates. J. Biol. Chem. 269:7059–61
    [Google Scholar]
  22. 22.  Martin A, Baker TA, Sauer RT 2008. Pore loops of the AAA+ ClpX machine grip substrates to drive translocation and unfolding. Nat. Struct. Mol. Biol. 15:1147–51
    [Google Scholar]
  23. 23.  Maillard RA, Chistol G, Sen M, Righini M, Tan J et al. 2011. ClpX(P) generates mechanical force to unfold and translocate its protein substrates. Cell 145:459–69
    [Google Scholar]
  24. 24.  Aubin-Tam ME, Olivares AO, Sauer RT, Baker TA, Lang MJ 2011. Single-molecule protein unfolding and translocation by an ATP-fueled proteolytic machine. Cell 145:257–67
    [Google Scholar]
  25. 25.  Beckwith R, Estrin E, Worden EJ, Martin A 2013. Reconstitution of the 26S proteasome reveals functional asymmetries in its AAA+ unfoldase. Nat. Struct. Mol. Biol. 20:1164–72
    [Google Scholar]
  26. 26.  Erales J, Hoyt MA, Troll F, Coffino P 2012. Functional asymmetries of proteasome translocase pore. J. Biol. Chem. 287:18535–43
    [Google Scholar]
  27. 27.  Lander GC, Estrin E, Matyskiela ME, Bashore C, Nogales E, Martin A 2012. Complete subunit architecture of the proteasome regulatory particle. Nature 482:186–91
    [Google Scholar]
  28. 28.  Lasker K, Förster F, Bohn S, Walzthoeni T, Villa E et al. 2012. Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach. PNAS 109:1380–87
    [Google Scholar]
  29. 29.  de Poot SAH, Tian G, Finley D 2017. Meddling with fate: the proteasomal deubiquitinating enzymes. J. Mol. Biol. 429:3525–45
    [Google Scholar]
  30. 30.  Verma R, Aravind L, Oania R, McDonald WH, Yates JR 3rd et al. 2002. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298:611–15
    [Google Scholar]
  31. 31.  Yao T, Cohen RE 2002. A cryptic protease couples deubiquitination and degradation by the proteasome. Nature 419:403–7
    [Google Scholar]
  32. 32.  Lee B-H, Lu Y, Prado MA, Shi Y, Tian G et al. 2016. USP14 deubiquitinates proteasome-bound substrates that are ubiquitinated at multiple sites. Nature 532:398–401
    [Google Scholar]
  33. 33.  Lam YA, Xu W, DeMartino GN, Cohen RE 1997. Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome. Nature 385:737–40
    [Google Scholar]
  34. 34.  Yao T, Song L, Xu W, DeMartino GN, Florens L et al. 2006. Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1. Nat. Cell Biol. 8:994–1002
    [Google Scholar]
  35. 35.  Hamazaki J, Iemura S-I, Natsume T, Yashiroda H, Tanaka K, Murata S 2006. A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. EMBO J 25:4524–36
    [Google Scholar]
  36. 36.  Qiu X-B, Ouyang S-Y, Li C-J, Miao S, Wang L, Goldberg AL 2006. hRpn13/ADRM1/GP110 is a novel proteasome subunit that binds the deubiquitinating enzyme, UCH37. EMBO J 25:5742–53
    [Google Scholar]
  37. 37.  Matyskiela ME, Lander GC, Martin A 2013. Conformational switching of the 26S proteasome enables substrate degradation. Nat. Struct. Mol. Biol. 20:781–88
    [Google Scholar]
  38. 38.  Sledz P, Unverdorben P, Beck F, Pfeifer G, Schweitzer A et al. 2013. Structure of the 26S proteasome with ATP-γS bound provides insights into the mechanism of nucleotide-dependent substrate translocation. PNAS 110:7264–69
    [Google Scholar]
  39. 39.  Unverdorben P, Beck F, Sledz P, Schweitzer A, Pfeifer G et al. 2014. Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome. PNAS 111:5544–49
    [Google Scholar]
  40. 40.  Wehmer M, Rudack T, Beck F, Aufderheide A, Pfeifer G et al. 2017. Structural insights into the functional cycle of the ATPase module of the 26S proteasome. PNAS 114:1305–10
    [Google Scholar]
  41. 41.  Luan B, Huang X, Wu J, Mei Z, Wang Y et al. 2016. Structure of an endogenous yeast 26S proteasome reveals two major conformational states. PNAS 113:2642–47
    [Google Scholar]
  42. 42.  Worden EJ, Dong KC, Martin A 2017. An AAA motor-driven mechanical switch in Rpn11 controls deubiquitination at the 26S proteasome. Mol. Cell 67:799–811
    [Google Scholar]
  43. 43.  Ding Z, Fu Z, Xu C, Wang Y, Wang Y et al. 2017. High-resolution cryo-EM structure of the proteasome in complex with ADP-AlFx. Cell Res 27:373–85
    [Google Scholar]
  44. 44.  Chen S, Wu J, Lu Y, Ma YB, Lee BH et al. 2016. Structural basis for dynamic regulation of the human 26S proteasome. PNAS 113:12991–96
    [Google Scholar]
  45. 45.  Zhu Y, Wang WL, Yu D, Ouyang Q, Lu Y, Mao Y 2017. Nucleotide-drive triple-state remodeling of the AAA-ATPase channel in the activated human 26S proteasome. bioRxiv https://doi.org/10.1101/132613
    [Crossref]
  46. 46.  Inobe T, Fishbain S, Prakash S, Matouschek A 2011. Defining the geometry of the two-component proteasome degron. Nat. Chem. Biol. 7:161–67
    [Google Scholar]
  47. 47.  Bashore C, Dambacher CM, Goodall EA, Matyskiela ME, Lander GC, Martin A 2015. Ubp6 deubiquitinase controls conformational dynamics and substrate degradation of the 26S proteasome. Nat. Struct. Mol. Biol. 22:712–19
    [Google Scholar]
  48. 48.  Beck F, Unverdorben P, Bohn S, Schweitzer A, Pfeifer G et al. 2012. Near-atomic resolution structural model of the yeast 26S proteasome. PNAS 109:14870–75
    [Google Scholar]
  49. 49.  Haselbach D, Schrader J, Lambrecht F, Henneberg F, Chari A, Stark H 2017. Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs. Nat. Commun. 8:15578
    [Google Scholar]
  50. 50.  Schweitzer A, Aufderheide A, Rudack T, Beck F, Pfeifer G et al. 2016. Structure of the human 26S proteasome at a resolution of 3.9 Å. PNAS 113:7816–21
    [Google Scholar]
  51. 51.  Huang X, Luan B, Wu J, Shi Y 2016. An atomic structure of the human 26S proteasome. Nat. Struct. Mol. Biol. 23:778–85
    [Google Scholar]
  52. 52.  da Fonseca PC, He J, Morris EP 2012. Molecular model of the human 26S proteasome. Mol. Cell 46:54–66
    [Google Scholar]
  53. 53.  Asano S, Fukuda Y, Beck F, Aufderheide A, Forster F et al. 2015. A molecular census of 26S proteasomes in intact neurons. Science 347:439–42
    [Google Scholar]
  54. 54.  Park S, Li X, Kim HM, Singh CR, Tian G et al. 2013. Reconfiguration of the proteasome during chaperone-mediated assembly. Nature 497:512–16
    [Google Scholar]
  55. 55.  Yu Y, Smith DM, Kim HM, Rodriguez V, Goldberg AL, Cheng Y 2010. Interactions of PAN's C-termini with archaeal 20S proteasome and implications for the eukaryotic proteasome-ATPase interactions. EMBO J 29:692–702
    [Google Scholar]
  56. 56.  Aufderheide A, Beck F, Stengel F, Hartwig M, Schweitzer A et al. 2015. Structural characterization of the interaction of Ubp6 with the 26S proteasome. PNAS 112:8626–31
    [Google Scholar]
  57. 57.  Hanna J, Hathaway NA, Tone Y, Crosas B, Elsasser S et al. 2006. Deubiquitinating enzyme Ubp6 functions noncatalytically to delay proteasomal degradation. Cell 127:99–111
    [Google Scholar]
  58. 58.  Peth A, Besche HC, Goldberg AL 2009. Ubiquitinated proteins activate the proteasome by binding to Usp14/Ubp6, which causes 20S gate opening. Mol. Cell 36:794–804
    [Google Scholar]
  59. 59.  Li X, Demartino GN 2009. Variably modulated gating of the 26S proteasome by ATP and polyubiquitin. Biochem. J. 421:397–404
    [Google Scholar]
  60. 60.  Smith DM, Fraga H, Reis C, Kafri G, Goldberg AL 2011. ATP binds to proteasomal ATPases in pairs with distinct functional effects, implying an ordered reaction cycle. Cell 144:526–38
    [Google Scholar]
  61. 61.  Liu CW, Li X, Thompson D, Wooding K, Chang TL et al. 2006. ATP binding and ATP hydrolysis play distinct roles in the function of 26S proteasome. Mol. Cell 24:39–50
    [Google Scholar]
  62. 62.  Peth A, Nathan JA, Goldberg AL 2013. The ATP costs and time required to degrade ubiquitinated proteins by the 26 S proteasome. J. Biol. Chem. 288:29215–22
    [Google Scholar]
  63. 63.  Peth A, Kukushkin N, Bosse M, Goldberg AL 2013. Ubiquitinated proteins activate the proteasomal ATPases by binding to Usp14 or Uch37 homologs. J. Biol. Chem. 288:7781–90
    [Google Scholar]
  64. 64.  Smith DM, Kafri G, Cheng Y, Ng D, Walz T, Goldberg AL 2005. ATP binding to PAN or the 26S ATPases causes association with the 20S proteasome, gate opening, and translocation of unfolded proteins. Mol. Cell 20:687–98
    [Google Scholar]
  65. 65.  Kleijnen MF, Roelofs J, Park S, Hathaway NA, Glickman M et al. 2007. Stability of the proteasome can be regulated allosterically through engagement of its proteolytic active sites. Nat. Struct. Mol. Biol. 14:1180–88
    [Google Scholar]
  66. 66.  Guo X, Wang X, Wang Z, Banerjee S, Yang J et al. 2016. Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis. Nat. Cell Biol. 18:202–12
    [Google Scholar]
  67. 67.  VerPlank JJS, Goldberg AL 2017. Regulating protein breakdown through proteasome phosphorylation. Biochem. J. 474:3355–71
    [Google Scholar]
  68. 68.  Guo X, Dixon JE 2016. The 26S proteasome: a cell cycle regulator regulated by cell cycle. Cell Cycle 15:875–76
    [Google Scholar]
  69. 69.  Tomko RJ Jr., Funakoshi M, Schneider K, Wang J, Hochstrasser M 2010. Heterohexameric ring arrangement of the eukaryotic proteasomal ATPases: implications for proteasome structure and assembly. Mol. Cell 38:393–403
    [Google Scholar]
  70. 70.  Tomko RJ Jr., Hochstrasser M 2011. Order of the proteasomal ATPases and eukaryotic proteasome assembly. Cell Biochem. Biophys. 60:13–20
    [Google Scholar]
  71. 71.  Inobe T, Genmei R 2015. N-terminal coiled-coil structure of ATPase subunits of 26S proteasome is crucial for proteasome function. PLOS ONE 10:e0134056
    [Google Scholar]
  72. 72.  Zhang F, Hu M, Tian G, Zhang P, Finley D et al. 2009. Structural insights into the regulatory particle of the proteasome from Methanocaldococcus jannaschii. Mol. Cell 34:473–84
    [Google Scholar]
  73. 73.  Glynn SE, Martin A, Nager AR, Baker TA, Sauer RT 2009. Structures of asymmetric ClpX hexamers reveal nucleotide-dependent motions in a AAA+ protein-unfolding machine. Cell 139:744–56
    [Google Scholar]
  74. 74.  Glynn SE, Nager AR, Baker TA, Sauer RT 2012. Dynamic and static components power unfolding in topologically closed rings of a AAA+ proteolytic machine. Nat. Struct. Mol. Biol. 19:616–22
    [Google Scholar]
  75. 75.  Gates SN, Yokom AL, Lin J, Jackrel ME, Rizo AN et al. 2017. Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104. Science 357:273–79
    [Google Scholar]
  76. 76.  Ripstein ZA, Huang R, Augustyniak R, Kay LE, Rubinstein JL 2017. Structure of a AAA+ unfoldase in the process of unfolding substrate. eLife 6:e25754
    [Google Scholar]
  77. 77.  Han H, Monroe N, Sundquist WI, Shen PS, Hill CP 2017. The AAA ATPase Vps4 binds ESCRT-III substrates through a repeating array of dipeptide-binding pockets. eLife 6:e31324
    [Google Scholar]
  78. 78.  Monroe N, Han H, Shen PS, Sundquist WI, Hill CP 2017. Structural basis of protein translocation by the Vps4-Vta1 AAA ATPase. eLife 6:e24487
    [Google Scholar]
  79. 79.  Puchades C, Rampello AJ, Shin M, Giuliano CJ, Wiseman RL et al. 2017. Structure of the mitochondrial inner membrane AAA+ protease YME1 gives insight into substrate processing. Science 358:eaao0464
    [Google Scholar]
  80. 80.  Thomsen ND, Berger JM 2009. Running in reverse: the structural basis for translocation polarity in hexameric helicases. Cell 139:523–34
    [Google Scholar]
  81. 81.  Zehr E, Szyk A, Piszczek G, Szczesna E, Zuo X, Roll-Mecak A 2017. Katanin spiral and ring structures shed light on power stroke for microtubule severing. Nat. Struct. Mol. Biol. 24:717–25
    [Google Scholar]
  82. 82.  Rubin DM, Glickman MH, Larsen CN, Dhruvakumar S, Finley D 1998. Active site mutants in the six regulatory particle ATPases reveal multiple roles for ATP in the proteasome. EMBO J 17:4909–19
    [Google Scholar]
  83. 83.  Hersch GL, Burton RE, Bolon DN, Baker TA, Sauer RT 2005. Asymmetric interactions of ATP with the AAA+ ClpX6 unfoldase: allosteric control of a protein machine. Cell 121:1017–27
    [Google Scholar]
  84. 84.  Yakamavich JA, Baker TA, Sauer RT 2008. Asymmetric nucleotide transactions of the HslUV protease. J. Mol. Biol. 380:946–57
    [Google Scholar]
  85. 85.  Nyquist K, Martin A 2014. Marching to the beat of the ring: polypeptide translocation by AAA+ proteases. Trends Biochem. Sci. 39:53–60
    [Google Scholar]
  86. 86.  Horwitz AA, Navon A, Groll M, Smith DM, Reis C, Goldberg AL 2007. ATP-induced structural transitions in PAN, the proteasome-regulatory ATPase complex in Archaea. J. Biol. Chem. 282:22921–29
    [Google Scholar]
  87. 87.  Kim YC, Snoberger A, Schupp J, Smith DM 2015. ATP binding to neighbouring subunits and intersubunit allosteric coupling underlie proteasomal ATPase function. Nat. Commun. 6:8520
    [Google Scholar]
  88. 88.  Iosefson O, Nager AR, Baker TA, Sauer RT 2015. Coordinated gripping of substrate by subunits of a AAA+ proteolytic machine. Nat. Chem. Biol. 11:201–6
    [Google Scholar]
  89. 89.  Iosefson O, Olivares AO, Baker TA, Sauer RT 2015. Dissection of axial-pore loop function during unfolding and translocation by a AAA+ proteolytic machine. Cell Rep 12:1032–41
    [Google Scholar]
  90. 90.  Prakash S, Tian L, Ratliff KS, Lehotzky RE, Matouschek A 2004. An unstructured initiation site is required for efficient proteasome-mediated degradation. Nat. Struct. Mol. Biol. 11:830–37
    [Google Scholar]
  91. 91.  Takeuchi J, Chen H, Coffino P 2007. Proteasome substrate degradation requires association plus extended peptide. EMBO J 26:123–31
    [Google Scholar]
  92. 92.  Chau V, Tobias JW, Bachmair A, Marriott D 1989. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243:1576–83
    [Google Scholar]
  93. 93.  Jin L, Williamson A, Banerjee S, Philipp I, Rape M 2008. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell 133:653–65
    [Google Scholar]
  94. 94.  Xu P, Duong DM, Seyfried NT, Cheng D, Xie Y et al. 2009. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 137:133–45
    [Google Scholar]
  95. 95.  Johnson ES, Ma PC, Ota IM, Varshavsky A 1995. A proteolytic pathway that recognizes ubiquitin as a degradation signal. J. Biol. Chem. 270:17442–56
    [Google Scholar]
  96. 96.  Kim W, Bennett EJ, Huttlin EL, Guo A, Li J et al. 2011. Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol. Cell 44:325–40
    [Google Scholar]
  97. 97.  Saeki Y, Kudo T, Sone T, Kikuchi Y, Yokosawa H et al. 2009. Lysine 63-linked polyubiquitin chain may serve as a targeting signal for the 26S proteasome. EMBO J 28:359–71
    [Google Scholar]
  98. 98.  Zhang D, Chen T, Ziv I, Rosenzweig R, Matiuhin Y et al. 2009. Together, Rpn10 and Dsk2 can serve as a polyubiquitin chain-length sensor. Mol. Cell 36:1018–33
    [Google Scholar]
  99. 99.  Riedinger C, Boehringer J, Trempe J-F, Lowe ED, Brown NR et al. 2010. Structure of Rpn10 and its interactions with polyubiquitin chains and the proteasome subunit Rpn12. J. Biol. Chem. 285:33992–4003
    [Google Scholar]
  100. 100.  Elsasser S, Chandler-Militello D, Müller B, Hanna J, Finley D 2004. Rad23 and Rpn10 serve as alternative ubiquitin receptors for the proteasome. J. Biol. Chem. 279:26817–22
    [Google Scholar]
  101. 101.  Mayor T, Graumann J, Bryan J, MacCoss MJ, Deshaies RJ 2007. Quantitative profiling of ubiquitylated proteins reveals proteasome substrates and the substrate repertoire influenced by the Rpn10 receptor pathway. Mol. Cell Proteom. 6:1885–95
    [Google Scholar]
  102. 102.  Lu Y, Lee BH, King RW, Finley D, Kirschner MW 2015. Substrate degradation by the proteasome: a single-molecule kinetic analysis. Science 348:1250834
    [Google Scholar]
  103. 103.  Shabek N, Herman-Bachinsky Y, Buchsbaum S, Lewinson O, Haj-Yahya M et al. 2012. The size of the proteasomal substrate determines whether its degradation will be mediated by mono- or polyubiquitylation. Mol. Cell 48:87–97
    [Google Scholar]
  104. 104.  Zhang M, Pickart CM, Coffino P 2003. Determinants of proteasome recognition of ornithine decarboxylase, a ubiquitin-independent substrate. EMBO J 22:1488–96
    [Google Scholar]
  105. 105.  Erales J, Coffino P 2014. Ubiquitin-independent proteasomal degradation. Biochim. Biophys. Acta 1843:216–21
    [Google Scholar]
  106. 106.  Janse DM, Crosas B, Finley D, Church GM 2004. Localization to the proteasome is sufficient for degradation. J. Biol. Chem. 279:21415–20
    [Google Scholar]
  107. 107.  Wilmington SR, Matouschek A 2016. An inducible system for rapid degradation of specific cellular proteins using proteasome adaptors. PLOS ONE 11:e0152679
    [Google Scholar]
  108. 108.  Fishbain S, Prakash S, Herrig A, Elsasser S, Matouschek A 2011. Rad23 escapes degradation because it lacks a proteasome initiation region. Nat. Commun. 2:192
    [Google Scholar]
  109. 109.  Yu H, Kago G, Yellman CM, Matouschek A 2016. Ubiquitin-like domains can target to the proteasome but proteolysis requires a disordered region. EMBO J 35:1522–36
    [Google Scholar]
  110. 110.  Kraut DA, Matouschek A 2011. Proteasomal degradation from internal sites favors partial proteolysis via remote domain stabilization. ACS Chem. Biol. 6:1087–95
    [Google Scholar]
  111. 111.  Prakash S, Inobe T, Hatch AJ, Matouschek A 2009. Substrate selection by the proteasome during degradation of protein complexes. Nat. Chem. Biol. 5:29–36
    [Google Scholar]
  112. 112.  Ye Y, Tang WK, Zhang T, Xia D 2017. A mighty “protein extractor” of the cell: structure and function of the p97/CDC48 ATPase. Front. Mol. Biosci. 4:39
    [Google Scholar]
  113. 113.  Bodnar N, Rapoport T 2017. Toward an understanding of the Cdc48/p97 ATPase. F1000Research 6:1318
    [Google Scholar]
  114. 114.  Blythe EE, Olson KC, Chau V, Deshaies RJ 2017. Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP*NPLOC4*UFD1L is enhanced by a mutation that causes multisystem proteinopathy. PNAS 114:E4380–88
    [Google Scholar]
  115. 115.  Bodnar NO, Rapoport TA 2017. Molecular mechanism of substrate processing by the Cdc48 ATPase complex. Cell 169:722–35
    [Google Scholar]
  116. 116.  Peth A, Uchiki T, Goldberg AL 2010. ATP-dependent steps in the binding of ubiquitin conjugates to the 26S proteasome that commit to degradation. Mol. Cell 40:671–81
    [Google Scholar]
  117. 117.  Fishbain S, Inobe T, Israeli E, Chavali S, Yu H et al. 2015. Sequence composition of disordered regions fine-tunes protein half-life. Nat. Struct. Mol. Biol. 22:214–21
    [Google Scholar]
  118. 118.  Kraut DA, Israeli E, Schrader EK, Patil A, Nakai K et al. 2012. Sequence- and species-dependence of proteasomal processivity. ACS Chem. Biol. 7:1444–53
    [Google Scholar]
  119. 119.  Yu H, Singh Gautam AK, Wilmington SR, Wylie D, Martinez-Fonts K et al. 2016. Conserved sequence preferences contribute to substrate recognition by the proteasome. J. Biol. Chem. 291:14526–39
    [Google Scholar]
  120. 120.  Tian L, Holmgren RA, Matouschek A 2005. A conserved processing mechanism regulates the activity of transcription factors Cubitus interruptus and NF-κB. Nat. Struct. Mol. Biol. 12:1045–53
    [Google Scholar]
  121. 121.  Piwko W, Jentsch S 2006. Proteasome-mediated protein processing by bidirectional degradation initiated from an internal site. Nat. Struct. Mol. Biol. 13:691–97
    [Google Scholar]
  122. 122.  Schreiner P, Chen X, Husnjak K, Randles L, Zhang N et al. 2008. Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interaction. Nature 453:548–52
    [Google Scholar]
  123. 123.  Sakata E, Bohn S, Mihalache O, Kiss P, Beck F et al. 2012. Localization of the proteasomal ubiquitin receptors Rpn10 and Rpn13 by electron cryomicroscopy. PNAS 109:1479–84
    [Google Scholar]
  124. 124.  Wang Q, Young P, Walters KJ 2005. Structure of S5a bound to monoubiquitin provides a model for polyubiquitin recognition. J. Mol. Biol. 348:727–39
    [Google Scholar]
  125. 125.  Lam YA, Lawson TG, Velayutham M, Zweier JL, Pickart CM 2002. A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal. Nature 416:763–67
    [Google Scholar]
  126. 126.  Elsasser S, Gali RR, Schwickart M, Larsen CN, Leggett DS et al. 2002. Proteasome subunit Rpn1 binds ubiquitin-like protein domains. Nat. Cell Biol. 4:725–30
    [Google Scholar]
  127. 127.  Funakoshi M, Sasaki T, Nishimoto T, Kobayashi H 2002. Budding yeast Dsk2p is a polyubiquitin-binding protein that can interact with the proteasome. PNAS 99:745–50
    [Google Scholar]
  128. 128.  Schauber C, Chen L, Tongaonkar P, Vega I, Lambertson D et al. 1998. Rad23 links DNA repair to the ubiquitin/proteasome pathway. Nature 391:715–18
    [Google Scholar]
  129. 129.  Kaplun L, Tzirkin R, Bakhrat A, Shabek N, Ivantsiv Y, Raveh D 2005. The DNA damage-inducible UbL-UbA protein Ddi1 participates in Mec1-mediated degradation of Ho endonuclease. Mol. Cell. Biol. 25:5355–62
    [Google Scholar]
  130. 130.  Hofmann K, Bucher P 1996. The UBA domain: a sequence motif present in multiple enzyme classes of the ubiquitination pathway. Trends Biochem. Sci. 21:172–73
    [Google Scholar]
  131. 131.  Chen X, Randles L, Shi K, Tarasov SG, Aihara H, Walters KJ 2016. Structures of Rpn1 T1:Rad23 and hRpn13:hPLIC2 reveal distinct binding mechanisms between substrate receptors and shuttle factors of the proteasome. Structure 24:1257–70
    [Google Scholar]
  132. 132.  Gomez TA, Kolawa N, Gee M, Sweredoski MJ, Deshaies RJ 2011. Identification of a functional docking site in the Rpn1 LRR domain for the UBA-UBL domain protein Ddi1. BMC Biol 9:33
    [Google Scholar]
  133. 133.  Walters KJ, Kleijnen MF, Goh AM, Wagner G, Howley PM 2002. Structural studies of the interaction between ubiquitin family proteins and proteasome subunit S5a. Biochemistry 41:1767–77
    [Google Scholar]
  134. 134.  Zhang N, Wang Q, Ehlinger A, Randles L, Lary JW et al. 2009. Structure of the S5a:K48-linked diubiquitin complex and its interactions with Rpn13. Mol. Cell 35:280–90
    [Google Scholar]
  135. 135.  Chen L, Madura K 2002. Rad23 promotes the targeting of proteolytic substrates to the proteasome. Mol. Cell. Biol. 22:4902–13
    [Google Scholar]
  136. 136.  Kim I, Mi K, Rao H 2004. Multiple interactions of Rad23 suggest a mechanism for ubiquitylated substrate delivery important in proteolysis. Mol. Biol. Cell 15:3357–65
    [Google Scholar]
  137. 137.  Hänzelmann P, Stingele J, Hofmann K, Schindelin H, Raasi S 2010. The yeast E4 ubiquitin ligase Ufd2 interacts with the ubiquitin-like domains of Rad23 and Dsk2 via a novel and distinct ubiquitin-like binding domain. J. Biol. Chem. 285:20390–98
    [Google Scholar]
  138. 138.  Itakura E, Zavodszky E, Shao S, Wohlever ML, Keenan RJ, Hegde RS 2016. Ubiquilins chaperone and triage mitochondrial membrane proteins for degradation. Mol. Cell 63:21–33
    [Google Scholar]
  139. 139.  Sims JJ, Haririnia A, Dickinson BC, Fushman D, Cohen RE 2009. Avid interactions underlie the K63-linked polyubiquitin binding specificities observed for UBA domains. Nat. Struct. Mol. Biol. 16:883–89
    [Google Scholar]
  140. 140.  Raasi S, Pickart CM 2003. Rad23 ubiquitin-associated domains (UBA) inhibit 26 S proteasome-catalyzed proteolysis by sequestering lysine 48-linked polyubiquitin chains. J. Biol. Chem. 278:8951–59
    [Google Scholar]
  141. 141.  Tsuchiya H, Ohtake F, Arai N, Kaiho A, Yasuda S et al. 2017. In vivo ubiquitin linkage-type analysis reveals that the Cdc48-Rad23/Dsk2 axis contributes to K48-linked chain specificity of the proteasome. Mol. Cell 66:488–502
    [Google Scholar]
  142. 142.  Saeki Y, Saitoh A, Toh-e A, Yokosawa H 2002. Ubiquitin-like proteins and Rpn10 play cooperative roles in ubiquitin-dependent proteolysis. Biochem. Biophys. Res. Commun. 293:986–92
    [Google Scholar]
  143. 143.  Verma R, Oania R, Graumann J, Deshaies RJ 2004. Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system. Cell 118:99–110
    [Google Scholar]
  144. 144.  Hamazaki J, Sasaki K, Kawahara H, Hisanaga S, Tanaka K, Murata S 2007. Rpn10-mediated degradation of ubiquitinated proteins is essential for mouse development. Mol. Cell. Biol. 27:6629–38
    [Google Scholar]
  145. 145.  Hamazaki J, Hirayama S, Murata S 2015. Redundant roles of Rpn10 and Rpn13 in recognition of ubiquitinated proteins and cellular homeostasis. PLOS Genet 11:e1005401
    [Google Scholar]
  146. 146.  Al-Shami A, Jhaver KG, Vogel P, Wilkins C, Humphries J et al. 2010. Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development. PLOS ONE 5:e13654
    [Google Scholar]
  147. 147.  Chojnacki M, Mansour W, Hameed DS, Singh RK, El Oualid F et al. 2017. Polyubiquitin-photoactivatable crosslinking reagents for mapping ubiquitin interactome identify Rpn1 as a proteasome ubiquitin-associating subunit. Cell Chem. Biol. 24:443–57
    [Google Scholar]
  148. 148.  Crosas B, Hanna J, Kirkpatrick DS, Zhang DP, Tone Y et al. 2006. Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell 127:1401–13
    [Google Scholar]
  149. 149.  Aguileta MA, Korac J, Durcan TM, Trempe J-F, Haber M et al. 2015. The E3 ubiquitin ligase parkin is recruited to the 26S proteasome via the proteasomal ubiquitin receptor Rpn13. J. Biol. Chem. 290:7492–505
    [Google Scholar]
  150. 150.  Leggett DS, Hanna J, Borodovsky A, Crosas B, Schmidt M et al. 2002. Multiple associated proteins regulate proteasome structure and function. Mol. Cell 10:495–507
    [Google Scholar]
  151. 151.  Cope GA, Suh GSB, Aravind L, Schwarz SE, Zipursky SL et al. 2002. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science 298:608–11
    [Google Scholar]
  152. 152.  Maytal-Kivity V, Reis N, Hofmann K, Glickman MH 2002. MPN+, a putative catalytic motif found in a subset of MPN domain proteins from eukaryotes and prokaryotes, is critical for Rpn11 function. BMC Biochem 3:28
    [Google Scholar]
  153. 153.  Guterman A, Glickman MH 2004. Complementary roles for Rpn11 and Ubp6 in deubiquitination and proteolysis by the proteasome. J. Biol. Chem. 279:1729–38
    [Google Scholar]
  154. 154.  Rinaldi T, Pick E, Gambadoro A, Zilli S, Maytal-Kivity V et al. 2004. Participation of the proteasomal lid subunit Rpn11 in mitochondrial morphology and function is mapped to a distinct C-terminal domain. Biochem. J. 381:275–85
    [Google Scholar]
  155. 155.  Worden EJ, Padovani C, Martin A 2014. Structure of the Rpn11–Rpn8 dimer reveals mechanisms of substrate deubiquitination during proteasomal degradation. Nat. Struct. Mol. Biol. 21:220–27
    [Google Scholar]
  156. 156.  Pathare GR, Nagy I, Sledz P, Anderson DJ, Zhou HJ et al. 2014. Crystal structure of the proteasomal deubiquitylation module Rpn8–Rpn11. PNAS 111:2984–89
    [Google Scholar]
  157. 157.  Dambacher CM, Worden EJ, Herzik MA, Martin A, Lander GC 2016. Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition. eLife 5:e13027
    [Google Scholar]
  158. 158.  Sato Y, Yoshikawa A, Yamagata A, Mimura H, Yamashita M et al. 2008. Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature 455:358–62
    [Google Scholar]
  159. 159.  Davies CW, Paul LN, Kim MI, Das C 2011. Structural and thermodynamic comparison of the catalytic domain of AMSH and AMSH-LP: nearly identical fold but different stability. J. Mol. Biol. 413:416–29
    [Google Scholar]
  160. 160.  Shrestha RK, Ronau JA, Davies CW, Guenette RG, Strieter ER et al. 2014. Insights into the mechanism of deubiquitination by JAMM deubiquitinases from cocrystal structures of the enzyme with the substrate and product. Biochemistry 53:3199–217
    [Google Scholar]
  161. 161.  Borodovsky A, Kessler BM, Casagrande R, Overkleeft HS, Wilkinson KD, Ploegh HL 2001. A novel active site‐directed probe specific for deubiquitylating enzymes reveals proteasome association of USP14. EMBO J 20:5187–96
    [Google Scholar]
  162. 162.  Kim HT, Goldberg AL 2017. The deubiquitinating enzyme Usp14 allosterically inhibits multiple proteasomal activities and ubiquitin-independent proteolysis. J. Biol. Chem. 292:9830–39
    [Google Scholar]
  163. 163.  Mansour W, Nakasone MA, von Delbrück M, Yu Z, Krutauz D et al. 2015. Disassembly of Lys11 and mixed linkage polyubiquitin conjugates provides insights into function of proteasomal deubiquitinases Rpn11 and Ubp6. J. Biol. Chem. 290:4688–704
    [Google Scholar]
  164. 164.  Hölzl H, Kapelari B, Kellermann J, Seemüller E, Sümegi M et al. 2000. The regulatory complex of Drosophila melanogaster 26S proteasomes. J. Cell Biol. 150:119–30
    [Google Scholar]
  165. 165.  Yao T, Song L, Jin J, Cai Y, Takahashi H et al. 2008. Distinct modes of regulation of the Uch37 deubiquitinating enzyme in the proteasome and in the Ino80 chromatin-remodeling complex. Mol. Cell 31:909–17
    [Google Scholar]
  166. 166.  Burgie SE, Bingman CA, Soni AB, Phillips GN 2012. Structural characterization of human Uch37. Proteins 80:649–54
    [Google Scholar]
  167. 167.  Sahtoe DD, van Dijk WJ, El Oualid F, Ekkebus R, Ovaa H, Sixma TK 2015. Mechanism of UCH-L5 activation and inhibition by DEUBAD domains in RPN13 and INO80G. Mol. Cell 57:887–900
    [Google Scholar]
  168. 168.  VanderLinden RT, Hemmis CW, Schmitt B, Ndoja A, Whitby FG et al. 2015. Structural basis for the activation and inhibition of the UCH37 deubiquitylase. Mol. Cell 57:901–11.
    [Google Scholar]
  169. 169.  Chen X, Lee B-H, Finley D, Walters KJ 2010. Structure of proteasome ubiquitin receptor hRpn13 and its activation by the scaffolding protein hRpn2. Mol. Cell 38:404–15
    [Google Scholar]
  170. 170.  Jacobson AD, MacFadden A, Wu Z, Peng J, Liu CW 2014. Autoregulation of the 26S proteasome by in situ ubiquitination. Mol. Biol. Cell 25:1824–35
    [Google Scholar]
  171. 171.  Zhang NY, Jacobson AD, MacFadden A, Liu CW 2011. Ubiquitin chain trimming recycles the substrate binding sites of the 26 S proteasome and promotes degradation of lysine 48-linked polyubiquitin conjugates. J. Biol. Chem. 286:25540–46
    [Google Scholar]
  172. 172.  Bohn S, Beck F, Sakata E, Walzthoeni T, Beck M et al. 2010. Structure of the 26S proteasome from Schizosaccharomyces pombe at subnanometer resolution. PNAS 107:20992–97
    [Google Scholar]
  173. 173.  Mueller TD, Feigon J 2003. Structural determinants for the binding of ubiquitin-like domains to the proteasome. EMBO J 22:4634–45
    [Google Scholar]
  174. 174.  VanderLinden RT, Hemmis CW, Yao T, Robinson H, Hill CP 2017. Structure and energetics of pairwise interactions between proteasome subunits RPN2, RPN13, and ubiquitin clarify a substrate recruitment mechanism. J. Biol. Chem. 292:9493–504
    [Google Scholar]
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