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The Ubiquitin Proteasome System with Its Checks and Balances

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Proteases in Physiology and Pathology

Abstract

Cells need to quickly change according to changing environment to survive, and for that, they must not just make new proteins but also degrade others equally promptly. For this purpose, cells have evolved the ubiquitin system, which consists of ubiquitin molecules which are used to tag proteins in a process called ubiquitination; E1, E2 and E3 enzymes which carry out the process of ubiquitination; and deubiquitinating enzymes (DUBs) that remove the ubiquitin from the substrate proteins in a process called deubiquitination. Ubiquitination involves various lysine residues on ubiquitin; among them K48 and K63 are the most significant and well understood. Ubiquitination with K48 linkage leads to degradation of substrate proteins by a multi-protein complex called proteasome. Proteasome-mediated degradation is involved in numerous different processes in cells, due to which defects in it are responsible for several diseases. But due to the high diversity of E3 enzymes and ubiquitin target proteins, there are many drug targets that can be utilized to treat diseases. This makes it vital to understand ubiquitin system for advancement of health care.

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References

  1. Goldstein G, Scheid M, Hammerling U et al (1975) Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proc Natl Acad Sci U S A 72:11–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ciechanover HA, Rose I (2006) The discovery of ubiquitin-mediated proteolysis. J Biol Chem 281(40):32

    Google Scholar 

  3. Ciechanover A, Elias S, Heller H et al (1980) Characterization of the heat-stable polypeptide of the ATP-dependent proteolytic system from reticulocytes. J Biol Chem 255:7525–7528

    CAS  PubMed  Google Scholar 

  4. Hershko A, Heller H, Elias S et al (1983) Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem 258:8206–8214

    CAS  PubMed  Google Scholar 

  5. Hershko A, Eytan E, Ciechanover A et al (1982) Immunochemical analysis of the turnover of ubiquitin-protein conjugates in intact cells. Relationship to the breakdown of abnormal proteins J Biol Chem 257:13964–13970

    CAS  PubMed  Google Scholar 

  6. Ulrich HD, Walden H (2010) Ubiquitin signalling in DNA replication and repair. Nat Rev Mol Cell Biol 11:479–489

    Article  CAS  PubMed  Google Scholar 

  7. Kodadek T (2010) No splicing, no dicing: non-proteolytic roles of the ubiquitin-proteasome system in transcription. J Biol Chem 285:2221–2226

    Article  CAS  PubMed  Google Scholar 

  8. Zhang Y (2003) Transcriptional regulation by histone ubiquitination and deubiquitination. Genes Dev 17:2733–2740

    Article  CAS  PubMed  Google Scholar 

  9. Kwapisz M, Cholbinski P, Hopper AK et al (2005) Rsp5 ubiquitin ligase modulates translation accuracy in yeast Saccharomyces cerevisiae. RNA 11:1710–1718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Spence J, Gali RR, Dittmar G et al (2000) Cell cycle-regulated modification of the ribosome by a variant multiubiquitin chain. Cell 102:67–76

    Article  CAS  PubMed  Google Scholar 

  11. Shcherbik N, Pestov DG (2010) Ubiquitin and ubiquitin-like proteins in the nucleolus: multitasking tools for a ribosome factory. Genes Cancer 1:681–689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen ZJ, Sun LJ (2009) Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 33:275–286

    Article  CAS  PubMed  Google Scholar 

  13. Kirkin V, McEwan DG, Novak I et al (2009) A role for ubiquitin in selective autophagy. Mol Cell 34:259–269

    Article  CAS  PubMed  Google Scholar 

  14. Mukhopadhyay D, Riezman H (2007) Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315(5809):201–205

    Article  CAS  PubMed  Google Scholar 

  15. Reinstein E, Ciechanover A (2006) Narrative review: protein degradation and human diseases: the ubiquitin connection. Ann Intern Med 145:676–684

    Article  PubMed  Google Scholar 

  16. Schwartz AL, Ciechanover A (2009) Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu Rev Pharmacol Toxicol 49:73–96

    Article  CAS  PubMed  Google Scholar 

  17. Nalepa G, Rolfe M, Harper JW (2006) Drug discovery in the ubiquitin-proteasome system. Nat Rev Drug Discov 5:596–613

    Article  CAS  PubMed  Google Scholar 

  18. Vijay-Kumar S, Bugg CE, Wilkinson KD, Cook WJ (1985) Three-dimensional structure of ubiquitin at 2.8 A0 resolution. Proc Natl Acad Sci U S A 82(11):3582–3585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vijay-Kumar S, Bugg CE, Cook WJ (1987) Structure of ubiquitin refined at 1.8 Å resolution. J Mol Biol 194:531–544

    Article  CAS  PubMed  Google Scholar 

  20. Ibarra-Molero B, Loladze VV, Makhatadze GI et al (1999) Thermal versus guanidine-induced unfolding of ubiquitin. An analysis in terms of the contributions from charge-charge interactions to protein stability. Biochemistry 38:8138–8149

    Article  CAS  PubMed  Google Scholar 

  21. Sundd M, Iverson N, Ibarra-Molero B et al (2002) Electrostatic interactions in ubiquitin: stabilization of carboxylates by lysine amino groups. Biochemistry 41:7586–7596

    Article  CAS  PubMed  Google Scholar 

  22. Sundd M, Robertson AD (2003) Rearrangement of charge-charge interactions in variant ubiquitins as detected by double-mutant cycles and NMR. J Mol Biol 332:927–936

    Article  CAS  PubMed  Google Scholar 

  23. Loladze VV, Ibarra-Molero B, Sanchez-Ruiz JM et al (1999) Engineering a thermostable protein via optimization of charge-charge interactions on the protein surface. Biochemistry 38:16419–16423

    Article  CAS  PubMed  Google Scholar 

  24. Loladze VV, Makhatadze GI (2002) Removal of surface charge-charge interactions from ubiquitin leaves the protein folded and very stable. Protein Sci 11:174–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Makhatadze GI, Loladze VV, Ermolenko DN et al (2003) Contribution of surface salt bridges to protein stability: guidelines for protein engineering. J Mol Biol 327:1135–1148

    Article  CAS  PubMed  Google Scholar 

  26. Loladze VV, Ermolenko DN, Makhatadze GI (2001) Heat capacity changes upon burial of polar and nonpolar groups in proteins. Protein Sci 10:1343–1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Loladze VV, Ermolenko DN, Makhatadze GI (2002) Thermodynamic consequences of burial of polar and non-polar amino acid residues in the protein interior. J Mol Biol 320(2):343–357

    Article  CAS  PubMed  Google Scholar 

  28. Khorasanizadeh S, Peters ID, Roder H (1996) Evidence for a three-state model of protein folding from kinetic analysis of ubiquitin variants with altered core residues. Nat Struct Biol 3(2):193–205

    Article  CAS  PubMed  Google Scholar 

  29. Sosnick TR, Dothager RS, Krantz BA (2004) Differences in the folding transition state of ubiquitin indicated by phi and psi analyses. Proc Natl Acad Sci U S A 101:17377–17382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Went HM, Jackson SE (2005) Ubiquitin folds through a highly polarized transition state. Protein Eng Des Sel 18:229–237

    Article  CAS  PubMed  Google Scholar 

  31. Thomas ST, Makhatadze GI (2000) Contribution of the 30/36 hydrophobic contact at the C-terminus of the alpha-helix to the stability of the ubiquitin molecule. Biochemistry 39:10275–10283

    Article  CAS  PubMed  Google Scholar 

  32. Sloper-Mould KE, Jemc JC, Pickart CM et al (2001) Distinct functional surface regions on ubiquitin. J Biol Chem 276:30483–30489

    Article  CAS  PubMed  Google Scholar 

  33. Beal R, Deveraux Q, Xia G et al (1996) Surface hydrophobic residues of multiubiquitin chains essential for proteolytic targeting. Proc Natl Acad Sci U S A 93:861–866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shih SC, Sloper-Mould KE, Hicke L (2000) Monoubiquitin carries a novel internalization signal that is appended to activated receptors. EMBO J 19:187–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schulman BA, Harper JW (2009) Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol 10:319–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gavilanes JG, Gonzalez de Buitrago G, Perez-Castells R, Rodriguez R (1982) Isolation, characterization, and amino acid sequence of a ubiquitin-like protein from insect eggs. J Biol Chem 257(17):10267–10270

    CAS  PubMed  Google Scholar 

  37. Watson DC, Levy WB, Dixon GH (1978) Free ubiquitin is a non-histone protein of trout testis chromatin. Nature 276:196–198

    Article  CAS  PubMed  Google Scholar 

  38. Schlesinger DH, Goldstein G, Niall HD (1975) The complete amino acid sequence of ubiquitin, an adenylate cyclase stimulating polypeptide probably universal in living cells. Biochemistry 14:2214–2218

    Article  CAS  PubMed  Google Scholar 

  39. Schlesinger DH, Goldstein G (1975) Molecular conservation of 74 amino acid sequence of ubiquitin between cattle and man. Nature 255:423–424

    Article  CAS  PubMed  Google Scholar 

  40. Wilkinson KD, Cox MJ, O’Connor LB et al (1986) Structure and activities of a variant ubiquitin sequence from bakers’ yeast. Biochemistry 25:4999–5004

    Article  CAS  PubMed  Google Scholar 

  41. Vierstra RD, Langan SM, Schaller GE (1986) Complete amino acid sequence of ubiquitin from the higher plant Avena sativa. Biochemistry 25(11):3105–3108

    Article  CAS  Google Scholar 

  42. Nath D, Shadan S (2009) The ubiquitin system. Nature 458:421

    Article  CAS  PubMed  Google Scholar 

  43. Pickart CM, Fushman D (2004) Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol 8:610–616

    Article  CAS  PubMed  Google Scholar 

  44. Hicke L (2001) Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2:195–201

    Article  CAS  PubMed  Google Scholar 

  45. Di Fiore PP, Polo S, Hofmann K (2003) When ubiquitin meets ubiquitin receptors: a signalling connection. Nat Rev Mol Cell Biol 4:491–497

    Article  PubMed  CAS  Google Scholar 

  46. Haglund K, Sigismund S, Polo S et al (2003a) Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 5:461–466

    Article  CAS  PubMed  Google Scholar 

  47. Haglund K, Di Fiore PP, Dikic I (2003b) Distinct monoubiquitin signals in receptor endocytosis. Trends Biochem Sci 28:598–603

    Article  CAS  PubMed  Google Scholar 

  48. Hicke L, Dunn R (2003) Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu Rev Cell Dev Biol 19:141–172

    Article  CAS  PubMed  Google Scholar 

  49. Johnson ES, Ma PC, Ota IM et al (1995) A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem 270:17442–17456

    Article  CAS  PubMed  Google Scholar 

  50. Peng J, Schwartz D, Elias JE et al (2003) A proteomics approach to understanding protein ubiquitination. Nat Biotechnol 21:921–926

    Article  CAS  PubMed  Google Scholar 

  51. Schimmel J, Larsen KM, Matic I et al (2008) The ubiquitin-proteasome system is a key component of the SUMO-2/3 cycle. Mol Cell Proteomics 7:2107–2122

    Article  CAS  PubMed  Google Scholar 

  52. Leidecker O, Matic I, Mahata B et al (2012) The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions. Cell Cycle 11:1142–1150

    Article  CAS  PubMed  Google Scholar 

  53. Ikeda F, Dikic I (2008) Atypical ubiquitin chains: new molecular signals. ‘Protein modifications: beyond the usual Suspects’ review series. EMBO Rep 9(6):536–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kim HT, Kim KP, Lledias F et al (2007) Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages. J Biol Chem 282:17375–17386

    Article  CAS  PubMed  Google Scholar 

  55. Kirisako T, Kamei K, Murata S et al (2006) A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J 25:4877–4887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Iwai K, Tokunaga F (2009) Linear polyubiquitination: a new regulator of NF-kappaB activation. EMBO Rep 10:706–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tokunaga F, Sakata S, Saeki Y et al (2009) Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 11:123–132

    Article  CAS  PubMed  Google Scholar 

  58. Rahighi S, Ikeda F, Kawasaki M et al (2009) Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell 136:1098–1109

    Article  CAS  PubMed  Google Scholar 

  59. Mishra P, Volety S, Rao Ch M et al (2009) Glutamate64 to glycine substitution in G1 beta-bulge of ubiquitin impairs function and stabilizes structure of the protein. J Biochem 146:563–569

    Article  CAS  PubMed  Google Scholar 

  60. Mishra P, Prabha CR, Rao Ch M et al (2011) Q2N and S65D substitutions of ubiquitin unravel functional significance of the invariant residues Gln2 and Ser65. Cell Biochem Biophys 61:619–628

    Article  CAS  PubMed  Google Scholar 

  61. Sharma M, Prabha CR (2015) Q2N and E64G double mutation of ubiquitin confers a stress sensitive phenotype on Saccharomyces cerevisiae. Indian J Exp Biol 53(9):617–620

    PubMed  Google Scholar 

  62. Sharma M, Prabha CR (2011) Construction and functional characterization of double and triple mutants of parallel beta-bulge of ubiquitin. Indian J Exp Biol 49(12):919–924

    CAS  PubMed  Google Scholar 

  63. Koyano F, Okatsu K, Kosako H et al (2014) Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510(7503):162–166

    CAS  PubMed  Google Scholar 

  64. Ratna Prabha C, Mishra P, Shahukar M (2010) Isolation of a dosage dependent lethal mutation in ubiquitin gene of Saccharomyces cereviae. Macromol Symp 287:89–94

    Article  CAS  Google Scholar 

  65. Doshi A, Mishra P, Sharma M, Prabha CR (2014) Functional characterization of dosage-dependent lethal mutation of ubiquitin in Saccharomyces cerevisiae. FEMS Yeast Res 14(7):1080–1089

    CAS  PubMed  Google Scholar 

  66. Haas AL, Rose IA (1982) The mechanism of ubiquitin activating enzyme. A kinetic and equilibrium analysis J Biol Chem 257:10329–10337

    CAS  PubMed  Google Scholar 

  67. Haas AL, Warms JV, Rose IA (1983) Ubiquitin adenylate: structure and role in ubiquitin activation. Biochemistry 22(19):4388–4394

    Article  CAS  PubMed  Google Scholar 

  68. Haas AL, Warms JV, Hershko A et al (1982) Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation J Biol Chem 257:2543–2548

    CAS  PubMed  Google Scholar 

  69. Ciechanover A, Elias S, Heller H et al (1982) “Covalent affinity” purification of ubiquitin-activating enzyme. J Biol Chem 257:2537–2542

    CAS  PubMed  Google Scholar 

  70. Ciechanover A, Heller H, Katz-Etzion R et al (1981) Activation of the heat-stable polypeptide of the ATP-dependent proteolytic system. Proc Natl Acad Sci USA 78:761–765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. VanDemark AP, Hill CP (2003) Two-stepping with E1. Nat Struct Biol 10:244–246

    Article  CAS  PubMed  Google Scholar 

  72. Lee I, Schindelin H (2008) Structural insights into E1-catalyzed ubiquitin activation and transfer to conjugating enzymes. Cell 134:268–278

    Article  CAS  PubMed  Google Scholar 

  73. Hong SB, Kim BW, Lee KE et al (2011) Insights into noncanonical E1 enzyme activation from the structure of autophagic E1 Atg7 with Atg8. Nat Struct Mol Biol 18:1323–1330

    Article  CAS  PubMed  Google Scholar 

  74. Pickart CM, Kasperek EM, Beal R et al (1994) Substrate properties of site-specific mutant ubiquitin protein (G76A) reveal unexpected mechanistic features of ubiquitin-activating enzyme (E1). J Biol Chem 269:7115–7123

    CAS  PubMed  Google Scholar 

  75. Mastrandrea LD, You J, Niles EG et al (1999) E2/E3-mediated assembly of lysine 29-linked polyubiquitin chains. J Biol Chem 274:27299–27306

    Article  CAS  PubMed  Google Scholar 

  76. Wilkinson KD, Smith SE, O’Connor L et al (1990) A specific inhibitor of the ubiquitin activating enzyme: synthesis and characterization of adenosyl-phospho-ubiquitinol, a nonhydrolyzable ubiquitin adenylate analogue. Biochemistry 29:7373–7380

    Article  CAS  PubMed  Google Scholar 

  77. Burch TJ, Haas AL (1994) Site-directed mutagenesis of ubiquitin. Differential roles for arginine in the interaction with ubiquitin-activating enzyme. Biochemistry 33:7300–7308

    Article  CAS  PubMed  Google Scholar 

  78. Whitby FG, Xia G, Pickart CM et al (1998) Crystal structure of the human ubiquitin-like protein NEDD8 and interactions with ubiquitin pathway enzymes. J Biol Chem 273:34983–34991

    Article  CAS  PubMed  Google Scholar 

  79. Ciechanover A, Finley D, Varshavsky A (1984) Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell 37:57–66

    Article  CAS  PubMed  Google Scholar 

  80. Aviel S, Winberg G, Massucci M et al (2000) Degradation of the epstein-barr virus latent membrane protein 1 (LMP1) by the ubiquitin-proteasome pathway. Targeting via ubiquitination of the N-terminal residue. J Biol Chem 275:23491–23499

    Article  CAS  PubMed  Google Scholar 

  81. Ghaboosi N, Deshaies RJ (2007a) A conditional yeast E1 mutant blocks the ubiquitin-proteasome pathway and reveals a role for ubiquitin conjugates in targeting Rad23 to the proteasome. Mol Biol Cell 18:1953–1963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Swanson R, Hochstrasser M (2000) A viable ubiquitin-activating enzyme mutant for evaluating ubiquitin system function in Saccharomyces cerevisiae. FEBS Lett 477:193–198

    Article  CAS  PubMed  Google Scholar 

  83. Jensen JP, Bates PW, Yang M et al (1995) Identification of a family of closely related human ubiquitin conjugating enzymes. J Biol Chem 270:30408–30414

    Article  CAS  PubMed  Google Scholar 

  84. Rajapurohitam V, Morales CR, El-Alfy M et al (1999) Activation of a UBC4-dependent pathway of ubiquitin conjugation during postnatal development of the rat testis. Dev Biol 212:217–228

    Article  CAS  PubMed  Google Scholar 

  85. Wefes I, Mastrandrea LD, Haldeman M et al (1995) Induction of ubiquitin-conjugating enzymes during terminal erythroid differentiation. Proc Natl Acad Sci U S A 92:4982–4986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Liu Z, Haas AL, Diaz LA et al (1996) Characterization of a novel keratinocyte ubiquitin carrier protein. J Biol Chem 271:2817–2822

    Article  CAS  PubMed  Google Scholar 

  87. Hauser HP, Bardroff M, Pyrowolakis G et al (1998) A giant ubiquitin-conjugating enzyme related to IAP apoptosis inhibitors. J Cell Biol 141:1415–1422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Huang L, Kinnucan E, Wang G et al (1999) Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade. Science 286:1321–1326

    Article  CAS  PubMed  Google Scholar 

  89. Zheng N, Wang P, Jeffrey PD et al (2000) Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell 102:533–539

    Article  CAS  PubMed  Google Scholar 

  90. Cook WJ, Jeffrey LC, Xu Y et al (1993) Tertiary structures of class I ubiquitin-conjugating enzymes are highly conserved: crystal structure of yeast Ubc4. Biochemistry 32:13809–13817

    Article  CAS  PubMed  Google Scholar 

  91. Worthylake DK, Prakash S, Prakash L et al (1998) Crystal structure of the Saccharomyces cerevisiae ubiquitin-conjugating enzyme Rad6 at 2.6 a resolution. J Biol Chem 273:6271–6276

    Article  CAS  PubMed  Google Scholar 

  92. Jiang F, Basavappa R (1999) Crystal structure of the cyclin-specific ubiquitin-conjugating enzyme from clam, E2-C, at 2.0 A resolution. Biochemistry 38:6471–6478

    Article  CAS  PubMed  Google Scholar 

  93. Miura T, Klaus W, Gsell B et al (1999) Characterization of the binding interface between ubiquitin and class I human ubiquitin-conjugating enzyme 2b by multidimensional heteronuclear NMR spectroscopy in solution. J Mol Biol 290:213–228

    Article  CAS  PubMed  Google Scholar 

  94. Arai R, Yoshikawa S, Murayama K et al (2006) Structure of human ubiquitin-conjugating enzyme E2 G2 (UBE2G2/UBC7). Acta Crystallogr Sect F Struct Biol Cryst Commun 62:330–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yamanaka A, Hatakeyama S, Kominami K et al (2000) Cell cycle-dependent expression of mammalian E2-C regulated by the anaphase-promoting complex/cyclosome. Mol Biol Cell 11:2821–2831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mathias N, Steussy CN, Goebl MG (1998) An essential domain within Cdc34p is required for binding to a complex containing Cdc4p and Cdc53p in Saccharomyces cerevisiae. J Biol Chem 273:4040–4045

    Article  CAS  PubMed  Google Scholar 

  97. Madura K, Dohmen RJ, Varshavsky A (1993) N-recognin/Ubc2 interactions in the N-end rule pathway. J Biol Chem 268:12046–12054

    CAS  PubMed  Google Scholar 

  98. Xie Y, Varshavsky A (1999) The E2-E3 interaction in the N-end rule pathway: the RING-H2 finger of E3 is required for the synthesis of multiubiquitin chain. EMBO J 18:6832–6844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yin Q, Lin SC, Lamothe B et al (2009) E2 interaction and dimerization in the crystal structure of TRAF6. Nat Struct Mol Biol 16:658–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang J, Taherbhoy AM et al (2010) Crystal structure of UBA2(ufd)-Ubc9: insights into E1-E2 interactions in Sumo pathways. PLoS One 5(12):15805

    Article  CAS  Google Scholar 

  101. Plechanovova A, Jaffray EG, Tatham MH et al (2012) Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489:115–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Pruneda JN, Littlefield PJ, Soss SE et al (2012) Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Mol Cell 47:933–942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dou H, Buetow L, Sibbet GJ et al (2012) BIRC7-E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nat Struct Mol Biol 19:876–883

    Article  CAS  PubMed  Google Scholar 

  104. Pickart CM (2001) Mechanisms underlying ubiquitination. Annu Rev Biochem 70:503–533

    Article  CAS  PubMed  Google Scholar 

  105. Ciechanover A, Ben-Saadon R (2004) N-terminal ubiquitination: more protein substrates join in. Trends Cell Biol 14:103–106

    Article  CAS  PubMed  Google Scholar 

  106. Deshaies RJ, Joazeiro CA (2009) RING domain E3 ubiquitin ligases. Annu Rev Biochem 78:399–434

    Article  CAS  PubMed  Google Scholar 

  107. Ogunjimi AA, Briant DJ, Pece-Barbara N et al (2005) Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol Cell 19(3):297–308

    Article  CAS  PubMed  Google Scholar 

  108. Verdecia MA, Joazeiro CA, Wells NJ et al (2003) Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Mol Cell 11:249–259

    Article  CAS  PubMed  Google Scholar 

  109. Kumar S, Talis AL, Howley PM (1999) Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination. J Biol Chem 274:18785–18792

    Article  CAS  PubMed  Google Scholar 

  110. Huibregtse JM, Yang JC, Beaudenon SL (1997a) The large subunit of RNA polymerase II is a substrate of the Rsp5 ubiquitin-protein ligase. Proc Natl Acad Sci U S A 94:3656–3661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Qiu L, Joazeiro C, Fang N et al (2000) Recognition and ubiquitination of notch by itch, a hect-type E3 ubiquitin ligase. J Biol Chem 275:35734–35737

    Article  CAS  PubMed  Google Scholar 

  112. Schwarz SE, Rosa JL, Scheffner M (1998) Characterization of human hect domain family members and their interaction with UbcH5 and UbcH7. J Biol Chem 273:12148–12154

    Article  CAS  PubMed  Google Scholar 

  113. Huibregtse JM, Scheffner M, Howley PM (1993) Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol Cell Biol 13:4918–4927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wilkinson KD (1997) Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J 11:1245–1256

    CAS  PubMed  Google Scholar 

  115. Nijman SM, Luna-Vargas MP, Velds A et al (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123:773–786

    Article  CAS  PubMed  Google Scholar 

  116. Wilkinson KD, Tashayev VL, O’Connor LB et al (1995) Metabolism of the polyubiquitin degradation signal: structure, mechanism, and role of isopeptidase T. Biochemistry 34:14535–14546

    Article  CAS  PubMed  Google Scholar 

  117. Piotrowski J, Beal R, Hoffman L et al (1997) Inhibition of the 26 S proteasome by polyubiquitin chains synthesized to have defined lengths. J Biol Chem 272:23712–23721

    Article  CAS  PubMed  Google Scholar 

  118. Baker RT, Board PG (1987) The human ubiquitin gene family: structure of a gene and pseudogenes from the Ub B subfamily. Nucleic Acids Res 15:443–463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ozkaynak E, Finley D, Solomon MJ et al (1987) The yeast ubiquitin genes: a family of natural gene fusions. EMBO J 6:1429–1439

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Wiborg O, Pedersen MS, Wind A et al (1985) The human ubiquitin multigene family: some genes contain multiple directly repeated ubiquitin coding sequences. EMBO J 4:755–759

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Rose IA, Warms JV (1983) An enzyme with ubiquitin carboxy-terminal esterase activity from reticulocytes. Biochemistry 22:4234–4237

    Article  CAS  PubMed  Google Scholar 

  122. Pickart CM, Rose IA (1985) Ubiquitin carboxyl-terminal hydrolase acts on ubiquitin carboxyl-terminal amides. J Biol Chem 260:7903–7910

    CAS  PubMed  Google Scholar 

  123. Amerik AY, Hochstrasser M (2004) Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 1695:189–207

    Article  CAS  PubMed  Google Scholar 

  124. Love KR, Catic A, Schlieker C et al (2007) Mechanisms, biology and inhibitors of deubiquitinating enzymes. Nat Chem Biol 3:697–705

    Article  CAS  PubMed  Google Scholar 

  125. Gan-Erdene T, Nagamalleswari K, Yin L et al (2003) Identification and characterization of DEN1, a deneddylase of the ULP family. J Biol Chem 278:28892–28900

    Article  CAS  PubMed  Google Scholar 

  126. Li SJ, Hochstrasser M (1999) A new protease required for cell-cycle progression in yeast. Nature 398:246–251

    Article  CAS  PubMed  Google Scholar 

  127. Li SJ, Hochstrasser M (2000) The yeast ULP2 (SMT4) gene encodes a novel protease specific for the ubiquitin-like Smt3 protein. Mol Cell Biol 20:2367–2377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kennedy RD, D’Andrea AD (2005) The Fanconi anemia/BRCA pathway: new faces in the crowd. Genes Dev 19:2925–2940

    Article  CAS  PubMed  Google Scholar 

  129. Daniel JA, Grant PA (2007) Multi-tasking on chromatin with the SAGA coactivator complexes. Mutat Res 618:135–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Song L, Rape M (2008) Reverse the curse--the role of deubiquitination in cell cycle control. Curr Opin Cell Biol 20:156–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Komada M (2008) Controlling receptor downregulation by ubiquitination and deubiquitination. Curr Drug Discov Technol 5:78–84

    Article  CAS  PubMed  Google Scholar 

  132. Adhikari A, Xu M, Chen ZJ (2007) Ubiquitin-mediated activation of TAK1 and IKK. Oncogene 26:3214–3226

    Article  CAS  PubMed  Google Scholar 

  133. Guterman A, Glickman MH (2004) Deubiquitinating enzymes are IN/(trinsic to proteasome function). Curr Protein Pept Sci 5:201–211

    Article  CAS  PubMed  Google Scholar 

  134. Schmidt M, Hanna J, Elsasser S et al (2005) Proteasome-associated proteins: regulation of a proteolytic machine. Biol Chem 386:725–737

    Article  CAS  PubMed  Google Scholar 

  135. Lindner HA (2007) Deubiquitination in virus infection. Virology 362:245–256

    Article  CAS  PubMed  Google Scholar 

  136. Rytkonen A, Holden DW (2007) Bacterial interference of ubiquitination and deubiquitination. Cell Host Microbe 1:13–22

    Article  CAS  PubMed  Google Scholar 

  137. Ye Z, Petrof EO, Boone D et al (2007) Salmonella effector AvrA regulation of colonic epithelial cell inflammation by deubiquitination. Am J Pathol 171:882–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Arguello MD, Hiscott J (2007) Ub surprised: viral ovarian tumor domain proteases remove ubiquitin and ISG15 conjugates. Cell Host Microbe 2:367–369

    Article  CAS  PubMed  Google Scholar 

  139. Barretto N, Jukneliene D, Ratia K et al (2005) The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J Virol 79:15189–15198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Iyer LM, Koonin EV, Aravind L (2004) Novel predicted peptidases with a potential role in the ubiquitin signaling pathway. Cell Cycle 3:1440–1450

    Article  CAS  PubMed  Google Scholar 

  141. Kattenhorn LM, Korbel GA, Kessler BM et al (2005) A deubiquitinating enzyme encoded by HSV-1 belongs to a family of cysteine proteases that is conserved across the family Herpesviridae. Mol Cell 19:547–557

    Article  CAS  PubMed  Google Scholar 

  142. Ratia K, Pegan S, Takayama J et al (2008) A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proc Natl Acad Sci U S A 105:16119–16124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Schlieker C, Korbel GA, Kattenhorn LM et al (2005) A deubiquitinating activity is conserved in the large tegument protein of the herpesviridae. J Virol 79:15582–15585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Sompallae R, Gastaldello S, Hildebrand S et al (2008) Epstein-barr virus encodes three bona fide ubiquitin-specific proteases. J Virol 82:10477–10486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sulea T, Lindner HA, Purisima EO et al (2005) Deubiquitination, a new function of the severe acute respiratory syndrome coronavirus papain-like protease? J Virol 79:4550–4551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Fischer JA (2003) Deubiquitinating enzymes: their roles in development, differentiation, and disease. Int Rev Cytol 229:43–72

    Article  CAS  PubMed  Google Scholar 

  147. Jiang YH, Beaudet AL (2004) Human disorders of ubiquitination and proteasomal degradation. Curr Opin Pediatr 16:419–426

    Article  PubMed  Google Scholar 

  148. Shanmugham A, Ovaa H (2008) DUBs and disease: activity assays for inhibitor development. Curr Opin Drug Discov Devel 11:688–696

    CAS  PubMed  Google Scholar 

  149. Komander D, Clague MJ, Urbé S (2009a) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10(8):550–563

    Article  CAS  PubMed  Google Scholar 

  150. Maiti TK, Permaul M, Boudreaux DA et al (2011) Crystal structure of the catalytic domain of UCHL5, a proteasome-associated human deubiquitinating enzyme, reveals an unproductive form of the enzyme. FEBS J 278:4917–4926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Hu M, Li P, Li M et al (2002) Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell 111:1041–1054

    Article  CAS  PubMed  Google Scholar 

  152. Komander D, Lord CJ, Scheel H et al (2008) The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Mol Cell 29:451–464

    Article  CAS  PubMed  Google Scholar 

  153. Hu M, Li P, Song L et al (2005) Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14. EMBO J 24:3747–3756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Avvakumov GV, Walker JR, Xue S et al (2006) Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8). J Biol Chem 281:38061–38070

    Article  CAS  PubMed  Google Scholar 

  155. Renatus M, Parrado SG, D’Arcy A et al (2006) Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. Structure 14:1293–1302

    Article  CAS  PubMed  Google Scholar 

  156. Albrecht M, Golatta M, Wullner U et al (2004) Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem 271:3155–3170

    Article  CAS  PubMed  Google Scholar 

  157. Mao Y, Senic-Matuglia F, Di Fiore PP et al (2005) Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc Natl Acad Sci U S A 102:12700–12705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Chai Y, Berke SS, Cohen RE et al (2004a) Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways. J Biol Chem 279:3605–3611

    Article  CAS  PubMed  Google Scholar 

  159. Nicastro G, Menon RP, Masino L et al (2005) The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. Proc Natl Acad Sci U S A 102:10493–10498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wang Q, Li L, Ye Y (2006) Regulation of retrotranslocation by p97-associated deubiquitinating enzyme ataxin-3. J Cell Biol 174:963–971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Riess O, Rub U, Pastore A et al (2008) SCA3: neurological features, pathogenesis and animal models. Cerebellum 7:125–137

    Article  CAS  PubMed  Google Scholar 

  162. Yao T, Cohen RE (2002a) A cryptic protease couples deubiquitination and degradation by the proteasome. Nature 419:403–407

    Article  CAS  PubMed  Google Scholar 

  163. McCullough J, Row PE, Lorenzo O et al (2006) Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM, a component of the multivesicular body-sorting machinery. Curr Biol 16:160–165

    Article  CAS  PubMed  Google Scholar 

  164. Cope GA, Suh GS, Aravind L et al (2002) Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science 298:608–611

    Article  CAS  PubMed  Google Scholar 

  165. Dong Y, Hakimi MA, Chen X et al (2003) Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell 12:1087–1099

    Article  CAS  PubMed  Google Scholar 

  166. Wang B, Elledge SJ (2007) Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci U S A 104:20759–20763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Shao G, Lilli DR, Patterson-Fortin J et al (2009) The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc Natl Acad Sci U S A 106:3166–3171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Cooper EM, Cutcliffe C, Kristiansen TZ et al (2009) K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO J 28:621–631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Sato Y, Yoshikawa A, Yamagata A et al (2008) Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature 455:358–362

    Article  CAS  PubMed  Google Scholar 

  170. Swanson KA, Kang RS, Stamenova SD, Hicke L, Radhakrishnan I (2003) Solution structure of Vps27 UIM ubiquitin complex important for endosomal sorting and receptor downregulation. EMBO J 22(18):4597–4606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Alam SL, Sun J, Payne M et al (2004) Ubiquitin interactions of NZF zinc fingers. EMBO J 23:1411–1421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kang RS, Daniels CM, Francis SA et al (2003) Solution structure of a CUE-ubiquitin complex reveals a conserved mode of ubiquitin binding. Cell 113:621–630

    Article  CAS  PubMed  Google Scholar 

  173. Prag G, Misra S, Jones EA et al (2003) Mechanism of ubiquitin recognition by the CUE domain of Vps9p. Cell 113:609–620

    Article  CAS  PubMed  Google Scholar 

  174. Ohno A, Jee J, Fujiwara K et al (2005) Structure of the UBA domain of Dsk2p in complex with ubiquitin molecular determinants for ubiquitin recognition. Structure 13:521–532

    Article  CAS  PubMed  Google Scholar 

  175. Prag G, Lee S, Mattera R, Arighi CN et al (2005) Structural mechanism for ubiquitinated-cargo recognition by the Golgi-localized, gamma-ear-containing, ADP-ribosylation-factor-binding proteins. Proc Natl Acad Sci U S A 102(7):2334–2339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Sundquist WI, Schubert HL, Kelly BN et al (2004) Ubiquitin recognition by the human TSG101 protein. Mol Cell 13:783–789

    Article  CAS  PubMed  Google Scholar 

  177. Teo H, Veprintsev DB, Williams RL (2004) Structural insights into endosomal sorting complex required for transport (ESCRT-I) recognition of ubiquitinated proteins. J Biol Chem 279:28689–28696

    Article  CAS  PubMed  Google Scholar 

  178. Lee S, Tsai YC, Mattera R et al (2006) Structural basis for ubiquitin recognition and autoubiquitination by Rabex-5. Nat Struct Mol Biol 13:264–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Reyes-Turcu FE, Horton JR, Mullally JE et al (2006) The ubiquitin binding domain ZnF UBP recognizes the C-terminal diglycine motif of unanchored ubiquitin. Cell 124:1197–1208

    Article  CAS  PubMed  Google Scholar 

  180. Praefcke GJ, Ford MG, Schmid EM et al (2004) Evolving nature of the AP2 alpha-appendage hub during clathrin-coated vesicle endocytosis. EMBO J 23(22):4371–4383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Haas AL, Bright PM (1985) The immunochemical detection and quantitation of intracellular ubiquitin-protein conjugates. J Biol Chem 260:12464–12473

    CAS  PubMed  Google Scholar 

  182. Wilkinson CR, Seeger M, Hartmann-Petersen R et al (2001) Proteins containing the UBA domain are able to bind to multi-ubiquitin chains. Nat Cell Biol 3:939–943

    Article  CAS  PubMed  Google Scholar 

  183. Raasi S, Orlov I, Fleming KG et al (2004) Binding of polyubiquitin chains to ubiquitin-associated (UBA) domains of HHR23A. J Mol Biol 341:1367–1379

    Article  CAS  PubMed  Google Scholar 

  184. Lange OF, Lakomek NA, Fares C et al (2008) Recognition dynamics up to microseconds revealed from an RDC-derived ubiquitin ensemble in solution. Science 320:1471–1475

    Article  CAS  PubMed  Google Scholar 

  185. Raasi S, Varadan R, Fushman D et al (2005) Diverse polyubiquitin interaction properties of ubiquitin-associated domains. Nat Struct Mol Biol 12:708–714

    Article  CAS  PubMed  Google Scholar 

  186. Komander D, Reyes-Turcu F, Licchesi JD et al (2009b) Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep 10:466–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Varadan R, Assfalg M, Raasi S et al (2005) Structural determinants for selective recognition of a Lys48-linked polyubiquitin chain by a UBA domain. Mol Cell 18:687–698

    Article  CAS  PubMed  Google Scholar 

  188. Sobhian B, Shao G, Lilli DR et al (2007) RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316:1198–1202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Sims JJ, Cohen RE (2009) Linkage-specific avidity defines the lysine 63-linked polyubiquitin-binding preference of rap80. Mol Cell 33:775–783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Puhler G, Weinkauf S, Bachmann L et al (1992) Subunit stoichiometry and three-dimensional arrangement in proteasomes from Thermoplasma acidophilum. EMBO J 11:1607–1616

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Grziwa A, Baumeister W, Dahlmann B et al (1991) Localization of subunits in proteasomes from Thermoplasma acidophilum by immunoelectron microscopy. FEBS Lett 290:186–190

    Article  CAS  PubMed  Google Scholar 

  192. Schauer TM, Nesper M, Kehl M et al (1993) Proteasomes from Dictyostelium discoideum: characterization of structure and function. J Struct Biol 111:135–147

    Article  CAS  PubMed  Google Scholar 

  193. Kopp F, Dahlmann B, Hendil KB (1993) Evidence indicating that the human proteasome is a complex dimer. J Mol Biol 229:14–19

    Article  CAS  PubMed  Google Scholar 

  194. Heinemeyer W, Trondle N, Albrecht G et al (1994) PRE5 and PRE6, the last missing genes encoding 20S proteasome subunits from yeast? Indication for a set of 14 different subunits in the eukaryotic proteasome core. Biochemistry 33:12229–12237

    Article  CAS  PubMed  Google Scholar 

  195. Lowe J, Stock D, Jap B et al (1995) Crystal structure of the 20S proteasome from the archaeon T. Acidophilum at 3.4 a resolution. Science 268:533–539

    Article  CAS  PubMed  Google Scholar 

  196. Groll M, Ditzel L, Lowe J et al (1997) Structure of 20S proteasome from yeast at 2.4 A0resolution. Nature 386:463–471

    Article  CAS  PubMed  Google Scholar 

  197. Seemuller E, Lupas A, Stock D et al (1995) Proteasome from Thermoplasma acidophilum: a threonine protease. Science 268:579–582

    Article  CAS  PubMed  Google Scholar 

  198. Baumeister W, Walz J, Zuhl F et al (1998) The proteasome: paradigm of a self-compartmentalizing protease. Cell 92:367–380

    Article  CAS  PubMed  Google Scholar 

  199. Heinemeyer W, Fischer M, Krimmer T et al (1997) The active sites of the eukaryotic 20 S proteasome and their involvement in subunit precursor processing. J Biol Chem 272:25200–25209

    Article  CAS  PubMed  Google Scholar 

  200. Chen P, Hochstrasser M (1996) Autocatalytic subunit processing couples active site formation in the 20S proteasome to completion of assembly. Cell 86:961–972

    Article  CAS  PubMed  Google Scholar 

  201. Jager S, Groll M, Huber R et al (1999) Proteasome beta-type subunits: unequal roles of propeptides in core particle maturation and a hierarchy of active site function. J Mol Biol 291:997–1013

    Article  CAS  PubMed  Google Scholar 

  202. Heinemeyer W, Ramos PC, Dohmen RJ (2004) The ultimate nanoscale mincer: assembly, structure and active sites of the 20S proteasome core. Cell Mol Life Sci 61:1562–1578

    Article  CAS  PubMed  Google Scholar 

  203. Bajorek M, Glickman MH (2004) Keepers at the final gates: regulatory complexes and gating of the proteasome channel. Cell Mol Life Sci 61:1579–1588

    Article  CAS  PubMed  Google Scholar 

  204. Groll M, Bajorek M, Kohler A et al (2000) A gated channel into the proteasome core particle. Nat Struct Biol 7:1062–1067

    Article  CAS  PubMed  Google Scholar 

  205. Hill CP, Masters EI, Whitby FG (2002) The 11S regulators of 20S proteasome activity. Curr Top Microbiol Immunol 268:73–89

    CAS  PubMed  Google Scholar 

  206. Glickman MH, Rubin DM, Coux O et al (1998) A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell 94:615–623

    Article  CAS  PubMed  Google Scholar 

  207. Finley D, Tanaka K, Mann C et al (1998) Unified nomenclature for subunits of the Saccharomyces cerevisiae proteasome regulatory particle. Trends Biochem Sci 23:244–245

    Article  CAS  PubMed  Google Scholar 

  208. Zhang F, Wu Z, Zhang P et al (2009a) Mechanism of substrate unfolding and translocation by the regulatory particle of the proteasome from Methanocaldococcus jannaschii. Mol Cell 34:485–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Smith DM, Chang SC, Park S et al (2007) Docking of the proteasomal ATPases’ carboxyl termini in the 20S proteasome’s alpha ring opens the gate for substrate entry. Mol Cell 27:731–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Gillette TG, Kumar B, Thompson D et al (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 283:31813–31822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Hanson PI, Whiteheart SW (2005) AAA+ proteins: have engine, will work. Nat Rev Mol Cell Biol 6(7):519–529

    Article  CAS  PubMed  Google Scholar 

  212. Hartmann-Petersen R, Tanaka K, Hendil KB (2001) Quaternary structure of the ATPase complex of human 26S proteasomes determined by chemical cross-linking. Arch Biochem Biophys 386:89–94

    Article  CAS  PubMed  Google Scholar 

  213. Djuranovic S, Hartmann MD, Habeck M et al (2009a) Structure and activity of the N-terminal substrate recognition domains in proteasomal ATPases. Mol Cell 34:580–590

    Article  CAS  PubMed  Google Scholar 

  214. Forster F, Lasker K, Beck F et al (2009) An atomic model AAA-ATPase/20S core particle sub-complex of the 26S proteasome. Biochem Biophys Res Commun 388:228–233

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Thrower JS, Hoffman L, Rechsteiner M, Pickart CM (2000) Recognition of the polyubiquitin proteolytic signal. EMBO J 19(1):94–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Rape M, Jentsch S (2002) Taking a bite: proteasomal protein processing. Nat Cell Biol 4:E113–E116

    Article  CAS  PubMed  Google Scholar 

  217. Asher G, Reuven N, Shaul Y (2006) 20S proteasomes and protein degradation “by default”. BioEssays 28:844–849

    Article  CAS  PubMed  Google Scholar 

  218. Zhang M, Pickart CM, Coffino P (2003) Determinants of proteasome recognition of ornithine decarboxylase, a ubiquitin-independent substrate. EMBO J 22:1488–1496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Asher G, Shaul Y (2005) p53 proteasomal degradation: poly-ubiquitination is not the whole story. Cell Cycle 4:1015–1018

    Article  CAS  PubMed  Google Scholar 

  220. Shringarpure R, Grune T, Mehlhase J et al (2003) Ubiquitin conjugation is not required for the degradation of oxidized proteins by proteasome. J Biol Chem 278:311–318

    Article  CAS  PubMed  Google Scholar 

  221. Deveraux Q, van Nocker S, Mahaffey D et al (1995) Inhibition of ubiquitin-mediated proteolysis by the Arabidopsis 26 S protease subunit S5a. J Biol Chem 270:29660–29663

    Article  CAS  PubMed  Google Scholar 

  222. Husnjak K, Elsasser S, Zhang N et al (2008) Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 453:481–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Wang Q, Young P, Walters KJ (2005) Structure of S5a bound to monoubiquitin provides a model for polyubiquitin recognition. J Mol Biol 348:727–739

    Article  CAS  PubMed  Google Scholar 

  224. Schreiner P, Chen X, Husnjak K et al (2008) Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interaction. Nature 453:548–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Tanaka K (2009) The proteasome: overview of structure and functions. Proc Jpn Acad Ser B Phys Biol Sci 85:12–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Elsasser S, Gali RR, Schwickart M et al (2002) Proteasome subunit Rpn1 binds ubiquitin-like protein domains. Nat Cell Biol 4:725–730

    Article  CAS  PubMed  Google Scholar 

  227. Lam YA, Lawson TG, Velayutham M et al (2002) A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal. Nature 416:763–767

    Article  CAS  PubMed  Google Scholar 

  228. Verma R, Aravind L, Oania R et al (2002) Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298:611–615

    Article  CAS  PubMed  Google Scholar 

  229. Zhang F, Hu M, Tian G et al (2009b) Structural insights into the regulatory particle of the proteasome from Methanocaldococcus jannaschii. Mol Cell 34:473–484

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  230. Lupas A, Baumeister W, Hofmann K (1997) A repetitive sequence in subunits of the 26S proteasome and 20S cyclosome (anaphase-promoting complex). Trends Biochem Sciv 22:195–196

    Article  CAS  Google Scholar 

  231. Kajava AV (2002) What curves alpha-solenoids? Evidence for an alpha-helical toroid structure of Rpn1 and Rpn2 proteins of the 26 S proteasome. J Biol Chem 277:49791–49798

    Article  CAS  PubMed  Google Scholar 

  232. Scheel H, Hofmann K (2005) Prediction of a common structural scaffold for proteasome lid, COP9-signalosome and eIF3 complexes. BMC Bioinformatics 6:71

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Muratani M, Tansey WP (2003) How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol 4:192–201

    Article  CAS  PubMed  Google Scholar 

  234. Thomas D, Tyers M (2000) Transcriptional regulation: kamikaze activators. Curr Biol 10:R341–R343

    Article  CAS  PubMed  Google Scholar 

  235. Finley D, Bartel B, Varshavsky A (1989) The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis. Nature 338:394–401

    Article  CAS  PubMed  Google Scholar 

  236. Deng L, Wang C, Spencer E et al (2000) Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103:351–361

    Article  CAS  PubMed  Google Scholar 

  237. Newton K, Matsumoto ML, Wertz IE et al (2008) Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies. Cell 134:668–678

    Article  CAS  PubMed  Google Scholar 

  238. Ting AT, Pimentel-Muinos FX, Seed B (1996) RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis. EMBO J 15:6189–6196

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Imai Y, Soda M, Hatakeyama S et al (2002) CHIP is associated with Parkin, a gene responsible for familial Parkinson’s disease, and enhances its ubiquitin ligase activity. Mol Cell 10:55–67

    Article  CAS  PubMed  Google Scholar 

  240. Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530

    Article  CAS  PubMed  Google Scholar 

  241. Xie Z, Klionsky DJ (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9:1102–1109

    Article  CAS  PubMed  Google Scholar 

  242. Imai Y, Soda M, Inoue H et al (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105:891–902

    Article  CAS  PubMed  Google Scholar 

  243. Zuccato C, Tartari M, Crotti A et al (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35:76–83

    Article  CAS  PubMed  Google Scholar 

  244. Gewin L, Myers H, Kiyono T et al (2004) Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex. Genes Dev 18:2269–2282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Huibregtse JM, Scheffner M, Howley PM (1991) A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J 10:4129–4135

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Kishino T, Lalande M, Wagstaff J (1997) UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 15:70–73

    Article  CAS  PubMed  Google Scholar 

  247. Matsuura T, Sutcliffe JS, Fang P et al (1997) De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet 15:74–77

    Article  CAS  PubMed  Google Scholar 

  248. Duensing S, Munger K (2004) Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int J Cancer 109:157–162

    Article  CAS  PubMed  Google Scholar 

  249. Ruffner H, Joazeiro CA, Hemmati D et al (2001) Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci U S A 98:5134–5139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Abrami L, Leppla SH, van der Goot FG (2006) Receptor palmitoylation and ubiquitination regulate anthrax toxin endocytosis. J Cell Biol 172:309–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Orth K, Xu Z, Mudgett MB et al (2000) Disruption of signaling by Yersinia effector YopJ, a ubiquitin-like protein protease. Science 290:1594–1597

    Article  CAS  PubMed  Google Scholar 

  252. Zhou H, Monack DM, Kayagaki N et al (2005) Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation. J Exp Med 202:1327–1332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Yadav, P., Doshi, A., Yoo, Y.J., Ratna Prabha, C. (2017). The Ubiquitin Proteasome System with Its Checks and Balances. In: Chakraborti, S., Dhalla, N. (eds) Proteases in Physiology and Pathology. Springer, Singapore. https://doi.org/10.1007/978-981-10-2513-6_26

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