1932

Abstract

Ubiquitin E3 ligases control every aspect of eukaryotic biology by promoting protein ubiquitination and degradation. At the end of a three-enzyme cascade, ubiquitin ligases mediate the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to specific substrate proteins. Early investigations of E3s of the RING (really interesting new gene) and HECT (homologous to the E6AP carboxyl terminus) types shed light on their enzymatic activities, general architectures, and substrate degron-binding modes. Recent studies have provided deeper mechanistic insights into their catalysis, activation, and regulation. In this review, we summarize the current progress in structure–function studies of ubiquitin ligases as well as exciting new discoveries of novel classes of E3s and diverse substrate recognition mechanisms. Our increased understanding of ubiquitin ligase function and regulation has provided the rationale for developing E3-targeting therapeutics for the treatment of human diseases.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-060815-014922
2017-06-20
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/biochem/86/1/annurev-biochem-060815-014922.html?itemId=/content/journals/10.1146/annurev-biochem-060815-014922&mimeType=html&fmt=ahah

Literature Cited

  1. Hershko A, Ciechanover A. 1.  1998. The ubiquitin system. Annu. Rev. Biochem. 67:425–79 [Google Scholar]
  2. Finley D. 2.  2009. Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu. Rev. Biochem. 78:477–513 [Google Scholar]
  3. Komander D, Rape M. 3.  2012. The ubiquitin code. Annu. Rev. Biochem. 81:203–29 [Google Scholar]
  4. Pickart CM. 4.  2001. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70:503–33 [Google Scholar]
  5. Deshaies RJ, Joazeiro CAP. 5.  2009. RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78:399–434 [Google Scholar]
  6. Deshaies RJ. 6.  1999. SCF and cullin/RING H2-based ubiquitin ligases. Annu. Rev. Cell Dev. Biol. 15:435–67 [Google Scholar]
  7. Zimmerman ES, Schulman BA, Zheng N. 7.  2010. Structural assembly of cullin-RING ubiquitin ligase complexes. Curr. Opin. Struct. Biol. 20:714–21 [Google Scholar]
  8. Chang L, Barford D. 8.  2014. Insights into the anaphase-promoting complex: a molecular machine that regulates mitosis. Curr. Opin. Struct. Biol. 29:1–9 [Google Scholar]
  9. Baer R, Ludwig T. 9.  2002. The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity. Curr. Opin. Genet. Dev. 12:86–91 [Google Scholar]
  10. Zheng N, Wang P, Jeffrey PD, Pavletich NP. 10.  2000. Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell 102:533–39 [Google Scholar]
  11. Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD. 11.  et al. 2002. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 416:703–9 [Google Scholar]
  12. Schulman BA, Carrano AC, Jeffrey PD, Bowen Z, Kinnucan ER. 12.  et al. 2000. Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex. Nature 408:381–86 [Google Scholar]
  13. Zhang M, Windheim M, Roe SM, Peggie M, Cohen P. 13.  et al. 2005. Chaperoned ubiquitylation—crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex. Mol. Cell 20:525–38 [Google Scholar]
  14. Mace PD, Linke K, Feltham R, Schumacher FR, Smith CA. 14.  et al. 2008. Structures of the cIAP2 RING domain reveal conformational changes associated with ubiquitin-conjugating enzyme (E2) recruitment. J. Biol. Chem. 283:31633–40 [Google Scholar]
  15. Bentley ML, Corn JE, Dong KC, Phung Q, Cheung TK, Cochran AG. 15.  2011. Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex. EMBO J 30:3285–97 [Google Scholar]
  16. Yin Q, Lin SC, Lamothe B, Lu M, Lo YC. 16.  et al. 2009. E2 interaction and dimerization in the crystal structure of TRAF6. Nat. Struct. Mol. Biol. 16:658–66 [Google Scholar]
  17. Ozkan E, Yu H, Deisenhofer J. 17.  2005. Mechanistic insight into the allosteric activation of a ubiquitin-conjugating enzyme by RING-type ubiquitin ligases. PNAS 102:18890–95 [Google Scholar]
  18. Benirschke RC, Thompson JR, Nominé Y, Wasielewski E, Juranić N. 18.  et al. 2010. Molecular basis for the association of human E4B U box ubiquitin ligase with E2-conjugating enzymes UbcH5c and Ubc4. Structure 18:955–65 [Google Scholar]
  19. Hamilton KS, Ellison MJ, Barber KR, Williams RS, Huzil JT. 19.  et al. 2001. Structure of a conjugating enzyme-ubiquitin thiolester intermediate reveals a novel role for the ubiquitin tail. Structure 9:897–904 [Google Scholar]
  20. Saha A, Lewis S, Kleiger G, Kuhlman B, Deshaies RJ. 20.  2011. Essential role for ubiquitin-ubiquitin-conjugating enzyme interaction in ubiquitin discharge from Cdc34 to substrate. Mol. Cell 42:75–83 [Google Scholar]
  21. Wickliffe KE, Lorenz S, Wemmer DE, Kuriyan J, Rape M. 21.  2011. The mechanism of linkage-specific ubiquitin chain elongation by a single-subunit E2. Cell 144:769–81 [Google Scholar]
  22. Plechanovová A, Jaffray EG, McMahon SA, Johnson KA, Navrátilová I. 22.  et al. 2011. Mechanism of ubiquitylation by dimeric RING ligase RNF4. Nat. Struct. Mol. Biol. 18:1052–59 [Google Scholar]
  23. Pruneda JN, Stoll KE, Bolton LJ, Brzovic PS, Klevit RE. 23.  2011. Ubiquitin in motion: structural studies of the ubiquitin-conjugating enzyme∼ubiquitin conjugate. Biochemistry 50:1624–33 [Google Scholar]
  24. Sakata E, Satoh T, Yamamoto S, Yamaguchi Y, Yagi-Utsumi M. 24.  et al. 2010. Crystal structure of UbcH5b∼ubiquitin intermediate: insight into the formation of the self-assembled E2∼Ub conjugates. Structure 18:138–47 [Google Scholar]
  25. Soss SE, Klevit RE, Chazin WJ. 25.  2013. Activation of UbcH5c∼Ub is the result of a shift in interdomain motions of the conjugate bound to U-box E3 ligase E4B. Biochemistry 52:2991–99 [Google Scholar]
  26. Pruneda JN, Littlefield PJ, Soss SE, Nordquist KA, Chazin WJ. 26.  et al. 2012. Structure of an E3:E2∼Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Mol. Cell 47:933–42 [Google Scholar]
  27. Plechanovová A, Jaffray EG, Tatham MH, Naismith JH, Hay RT. 27.  2012. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489:115–20 [Google Scholar]
  28. Dou H, Buetow L, Sibbet GJ, Cameron K, Huang DT. 28.  2012. BIRC7-E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nat. Struct. Mol. Biol. 19:876–83 [Google Scholar]
  29. Dou H, Buetow L, Sibbet GJ, Cameron K, Huang DT. 29.  2013. Essentiality of a non-RING element in priming donor ubiquitin for catalysis by a monomeric E3. Nat. Struct. Mol. Biol. 20:982–86 [Google Scholar]
  30. Buetow L, Gabrielsen M, Anthony NG, Dou H, Patel A. 30.  et al. 2015. Activation of a primed RING E3-E2-ubiquitin complex by non-covalent ubiquitin. Mol. Cell 58:297–310 [Google Scholar]
  31. Branigan E, Plechanovová A, Jaffray EG, Naismith JH, Hay RT. 31.  2015. Structural basis for the RING-catalyzed synthesis of K63-linked ubiquitin chains. Nat. Struct. Mol. Biol. 22:597–602 [Google Scholar]
  32. Reverter D, Lima CD. 32.  2005. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. Nature 435:687–92 [Google Scholar]
  33. Scott DC, Sviderskiy VO, Monda JK, Lydeard JR, Cho SE. 33.  et al. 2014. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 157:1671–84 [Google Scholar]
  34. Berndsen CE, Wiener R, Yu IW, Ringel AE, Wolberger C. 34.  2013. A conserved asparagine has a structural role in ubiquitin-conjugating enzymes. Nat. Chem. Biol. 9:154–56 [Google Scholar]
  35. Wu PY, Hanlon M, Eddins M, Tsui C, Rogers RS. 35.  et al. 2003. A conserved catalytic residue in the ubiquitin-conjugating enzyme family. EMBO J 22:5241–50 [Google Scholar]
  36. Yunus AA, Lima CD. 36.  2006. Lysine activation and functional analysis of E2-mediated conjugation in the SUMO pathway. Nat. Struct. Mol. Biol. 13:491–99 [Google Scholar]
  37. Brzovic PS, Lissounov A, Christensen DE, Hoyt DW, Klevit RE. 37.  2006. A UbcH5/ubiquitin noncovalent complex is required for processive BRCA1-directed ubiquitination. Mol. Cell 21:873–80 [Google Scholar]
  38. Das R, Mariano J, Tsai YC, Kalathur RC, Kostova Z. 38.  et al. 2009. Allosteric activation of E2-RING finger-mediated ubiquitylation by a structurally defined specific E2-binding region of gp78. Mol. Cell 34:674–85 [Google Scholar]
  39. Das R, Liang YH, Mariano J, Li J, Huang T. 39.  et al. 2013. Allosteric regulation of E2:E3 interactions promote a processive ubiquitination machine. EMBO J 32:2504–16 [Google Scholar]
  40. Wright JD, Mace PD, Day CL. 40.  2016. Secondary ubiquitin-RING docking enhances Arkadia and Ark2C E3 ligase activity. Nat. Struct. Mol. Biol. 23:45–52 [Google Scholar]
  41. Pierce NW, Kleiger G, Shan SO, Deshaies RJ. 41.  2009. Detection of sequential polyubiquitylation on a millisecond timescale. Nature 462:615–19 [Google Scholar]
  42. Stewart MD, Ritterhoff T, Klevit RE, Brzovic PS. 42.  2016. E2 enzymes: more than just middle men. Cell Res 26:423–40 [Google Scholar]
  43. Christensen DE, Brzovic PS, Klevit RE. 43.  2007. E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages. Nat. Struct. Mol. Biol. 14:941–48 [Google Scholar]
  44. Wu Y, Lin JC, Piluso LG, Dhahbi JM, Bobadilla S. 44.  et al. 2014. Phosphorylation of p53 by TAF1 inactivates p53-dependent transcription in the DNA damage response. Mol. Cell 53:63–74 [Google Scholar]
  45. Jin L, Williamson A, Banerjee S, Philipp I, Rape M. 45.  2008. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell 133:653–65 [Google Scholar]
  46. Wu T, Merbl Y, Huo Y, Gallop JL, Tzur A, Kirschner MW. 46.  2010. UBE2S drives elongation of K11-linked ubiquitin chains by the anaphase-promoting complex. PNAS 107:1355–60 [Google Scholar]
  47. Garnett MJ, Mansfeld J, Godwin C, Matsusaka T, Wu J. 47.  et al. 2009. UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Nat. Cell Biol. 11:1363–69 [Google Scholar]
  48. Williamson A, Wickliffe KE, Mellone BG, Song L, Karpen GH, Rape M. 48.  2009. Identification of a physiological E2 module for the human anaphase-promoting complex. PNAS 106:18213–18 [Google Scholar]
  49. Petroski MD, Deshaies RJ. 49.  2005. Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase complex SCF-Cdc34. Cell 123:1107–20 [Google Scholar]
  50. Saha A, Deshaies RJ. 50.  2008. Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation. Mol. Cell 32:21–31 [Google Scholar]
  51. Wu K, Kovacev J, Pan ZQ. 51.  2010. Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for polyubiquitination on a SCF substrate. Mol. Cell 37:784–96 [Google Scholar]
  52. Kleiger G, Saha A, Lewis S, Kuhlman B, Deshaies RJ. 52.  2009. Rapid E2-E3 assembly and disassembly enable processive ubiquitylation of cullin-RING ubiquitin ligase substrates. Cell 139:957–68 [Google Scholar]
  53. Kelly A, Wickliffe KE, Song L, Fedrigo I, Rape M. 53.  2014. Ubiquitin chain elongation requires E3-dependent tracking of the emerging conjugate. Mol. Cell 56:232–45 [Google Scholar]
  54. Brown NG, Watson ER, Weissmann F, Jarvis MA, VanderLinden R. 54.  et al. 2014. Mechanism of polyubiquitination by human anaphase-promoting complex: RING repurposing for ubiquitin chain assembly. Mol. Cell 56:246–60 [Google Scholar]
  55. Brown NG, VanderLinden R, Watson ER, Weissmann F, Ordureau A. 55.  et al. 2016. Dual RING E3 architectures regulate multiubiquitination and ubiquitin chain elongation by APC/C. Cell 165:1440–53 [Google Scholar]
  56. Lu Y, Wang W, Kirschner MW. 56.  2015. Specificity of the anaphase-promoting complex: a single-molecule study. Science 348:1248737 [Google Scholar]
  57. Rotin D, Kumar S. 57.  2009. Physiological functions of the HECT family of ubiquitin ligases. Nat. Rev. Mol. Cell Biol. 10:398–409 [Google Scholar]
  58. Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM. 58.  et al. 1999. Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade. Science 286:1321–26 [Google Scholar]
  59. Verdecia MA, Joazeiro CA, Wells NJ, Ferrer JL, Bowman ME. 59.  et al. 2003. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Mol. Cell 11:249–59 [Google Scholar]
  60. Ogunjimi AA, Briant DJ, Pece-Barbara N, Le Roy C, Di Guglielmo GM. 60.  et al. 2005. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol. Cell 19:297–308 [Google Scholar]
  61. Kamadurai HB, Souphron J, Scott DC, Duda DM, Miller DJ. 61.  et al. 2009. Insights into ubiquitin transfer cascades from a structure of a UbcH5B∼Ubiquitin-HECTNEDD4L complex. Mol. Cell 36:1095–102 [Google Scholar]
  62. Maspero E, Valentini E, Mari S, Cecatiello V, Soffientini P. 62.  et al. 2013. Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming. Nat. Struct. Mol. Biol. 20:696–701 [Google Scholar]
  63. Kamadurai HB, Qiu Y, Deng A, Harrison JS, Macdonald C. 63.  et al. 2013. Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3. eLife 2:e00828 [Google Scholar]
  64. Kim HC, Huibregtse JM. 64.  2009. Polyubiquitination by HECT E3s and the determinants of chain type specificity. Mol. Cell. Biol. 29:3307–18 [Google Scholar]
  65. French ME, Kretzmann BR, Hicke L. 65.  2009. Regulation of the RSP5 ubiquitin ligase by an intrinsic ubiquitin-binding site. J. Biol. Chem. 284:12071–79 [Google Scholar]
  66. Kim HC, Steffen AM, Oldham ML, Chen J, Huibregtse JM. 66.  2011. Structure and function of a HECT domain ubiquitin-binding site. EMBO Rep 12:334–41 [Google Scholar]
  67. Ogunjimi AA, Wiesner S, Briant DJ, Varelas X, Sicheri F. 67.  et al. 2010. The ubiquitin binding region of the Smurf HECT domain facilitates polyubiquitylation and binding of ubiquitylated substrates. J. Biol. Chem. 285:6308–15 [Google Scholar]
  68. Maspero E, Mari S, Valentini E, Musacchio A, Fish A. 68.  et al. 2011. Structure of the HECT:ubiquitin complex and its role in ubiquitin chain elongation. EMBO Rep 12:342–49 [Google Scholar]
  69. Ernst A, Avvakumov G, Tong J, Fan Y, Zhao Y. 69.  et al. 2013. A strategy for modulation of enzymes in the ubiquitin system. Science 339:590–95 [Google Scholar]
  70. Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A. 70.  et al. 2016. System-wide modulation of HECT E3 ligases with selective ubiquitin variant probes. Mol. Cell 62:121–36 [Google Scholar]
  71. Wenzel DM, Lissounov A, Brzovic PS, Klevit RE. 71.  2011. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 474:105–8 [Google Scholar]
  72. Huang A, de Jong RN, Wienk H, Winkler GS, Timmers HT, Boelens R. 72.  2009. E2-c-Cbl recognition is necessary but not sufficient for ubiquitination activity. J. Mol. Biol. 385:507–19 [Google Scholar]
  73. Brzovic PS, Keeffe JR, Nishikawa H, Miyamoto K, Fox D. 73.  et al. 2003. Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. PNAS 100:5646–51 [Google Scholar]
  74. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S. 74.  et al. 2000. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. 25:302–5 [Google Scholar]
  75. Smit JJ, Monteferrario D, Noordermeer SM, van Dijk WJ, van der Reijden BA, Sixma TK. 75.  2012. The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension. EMBO J 31:3833–44 [Google Scholar]
  76. Stieglitz B, Morris-Davies AC, Koliopoulos MG, Christodoulou E, Rittinger K. 76.  2012. LUBAC synthesizes linear ubiquitin chains via a thioester intermediate. EMBO Rep 13:840–46 [Google Scholar]
  77. Spratt DE, Walden H, Shaw GS. 77.  2014. RBR E3 ubiquitin ligases: new structures, new insights, new questions. Biochem. J. 458:421–37 [Google Scholar]
  78. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y. 78.  et al. 1998. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–8 [Google Scholar]
  79. Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H. 79.  et al. 2006. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J 25:4877–87 [Google Scholar]
  80. Aguilera M, Oliveros M, Martínez-Padrón M, Barbas JA, Ferrús A. 80.  2000. Ariadne-1: a vital Drosophila gene is required in development and defines a new conserved family of ring-finger proteins. Genetics 155:1231–44 [Google Scholar]
  81. Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C. 81.  et al. 2011. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471:637–41 [Google Scholar]
  82. Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M. 82.  et al. 2011. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471:633–36 [Google Scholar]
  83. Chaugule VK, Burchell L, Barber KR, Sidhu A, Leslie SJ. 83.  et al. 2011. Autoregulation of Parkin activity through its ubiquitin-like domain. EMBO J 30:2853–67 [Google Scholar]
  84. Trempe JF, Sauvé V, Grenier K, Seirafi M, Tang MY. 84.  et al. 2013. Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science 340:1451–55 [Google Scholar]
  85. Riley BE, Lougheed JC, Callaway K, Velasquez M, Brecht E. 85.  et al. 2013. Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases. Nat. Commun. 4:1982 [Google Scholar]
  86. Wauer T, Komander D. 86.  2013. Structure of the human Parkin ligase domain in an autoinhibited state. EMBO J 32:2099–112 [Google Scholar]
  87. Duda DM, Olszewski JL, Schuermann JP, Kurinov I, Miller DJ. 87.  et al. 2013. Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoinhibition of an Ariadne-family E3 and insights into ligation mechanism. Structure 21:1030–41 [Google Scholar]
  88. Lechtenberg BC, Rajput A, Sanishvili R, Dobaczewska MK, Ware CF. 88.  et al. 2016. Structure of a HOIP/E2∼ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature 529:546–50 [Google Scholar]
  89. Wauer T, Simicek M, Schubert A, Komander D. 89.  2015. Mechanism of phospho-ubiquitin-induced PARKIN activation. Nature 524:370–74 [Google Scholar]
  90. Stieglitz B, Rana RR, Koliopoulos MG, Morris-Davies AC, Schaeffer V. 90.  et al. 2013. Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature 503:422–26 [Google Scholar]
  91. Janjusevic R, Abramovitch RB, Martin GB, Stebbins CE. 91.  2006. A bacterial inhibitor of host programmed cell death defenses is an E3 ubiquitin ligase. Science 311:222–26 [Google Scholar]
  92. Wu B, Skarina T, Yee A, Jobin MC, Dileo R. 92.  et al. 2010. NleG type 3 effectors from enterohaemorrhagic Escherichia coli are U-Box E3 ubiquitin ligases. PLOS Pathog 6:e1000960 [Google Scholar]
  93. Lin DY, Diao J, Chen J. 93.  2012. Crystal structures of two bacterial HECT-like E3 ligases in complex with a human E2 reveal atomic details of pathogen-host interactions. PNAS 109:1925–30 [Google Scholar]
  94. Lin DY, Diao J, Zhou D, Chen J. 94.  2011. Biochemical and structural studies of a HECT-like ubiquitin ligase from Escherichia coli O157:H7. J. Biol. Chem. 286:441–49 [Google Scholar]
  95. Diao J, Zhang Y, Huibregtse JM, Zhou D, Chen J. 95.  2008. Crystal structure of SopA, a Salmonella effector protein mimicking a eukaryotic ubiquitin ligase. Nat. Struct. Mol. Biol. 15:65–70 [Google Scholar]
  96. Rohde JR, Breitkreutz A, Chenal A, Sansonetti PJ, Parsot C. 96.  2007. Type III secretion effectors of the IpaH family are E3 ubiquitin ligases. Cell Host Microbe 1:77–83 [Google Scholar]
  97. Zhu Y, Li H, Hu L, Wang J, Zhou Y. 97.  et al. 2008. Structure of a Shigella effector reveals a new class of ubiquitin ligases. Nat. Struct. Mol. Biol. 15:1302–8 [Google Scholar]
  98. Singer AU, Rohde JR, Lam R, Skarina T, Kagan O. 98.  et al. 2008. Structure of the Shigella T3SS effector IpaH defines a new class of E3 ubiquitin ligases. Nat. Struct. Mol. Biol. 15:1293–301 [Google Scholar]
  99. Quezada CM, Hicks SW, Galán JE, Stebbins CE. 99.  2009. A family of Salmonella virulence factors functions as a distinct class of autoregulated E3 ubiquitin ligases. PNAS 106:4864–69 [Google Scholar]
  100. Chou YC, Keszei AF, Rohde JR, Tyers M, Sicheri F. 100.  2012. Conserved structural mechanisms for autoinhibition in IpaH ubiquitin ligases. J. Biol. Chem. 287:268–75 [Google Scholar]
  101. Keszei AF, Tang X, McCormick C, Zeqiraj E, Rohde JR. 101.  et al. 2014. Structure of an SspH1-PKN1 complex reveals the basis for host substrate recognition and mechanism of activation for a bacterial E3 ubiquitin ligase. Mol. Cell. Biol. 34:362–73 [Google Scholar]
  102. Zouhir S, Bernal-Bayard J, Cordero-Alba M, Cardenal-Muñoz E, Guimaraes B. 102.  et al. 2014. The structure of the Slrp-Trx1 complex sheds light on the autoinhibition mechanism of the type III secretion system effectors of the NEL family. Biochem. J. 464:135–44 [Google Scholar]
  103. Qiu J, Sheedlo MJ, Yu K, Tan Y, Nakayasu ES. 103.  et al. 2016. Ubiquitination independent of E1 and E2 enzymes by bacterial effectors. Nature 533:120–24 [Google Scholar]
  104. Bhogaraju S, Kalayil S, Liu Y, Bonn F, Colby T. 104.  et al. 2016. Phosphoribosylation of ubiquitin promotes serine ubiquitination and impairs conventional ubiquitination. Cell 167:1636–49 [Google Scholar]
  105. Marmor MD, Yarden Y. 105.  2004. Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 23:2057–70 [Google Scholar]
  106. Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY. 106.  et al. 1999. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol. Cell 4:1029–40 [Google Scholar]
  107. Kassenbrock CK, Anderson SM. 107.  2004. Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations. J. Biol. Chem. 279:28017–27 [Google Scholar]
  108. Ryan PE, Sivadasan-Nair N, Nau MM, Nicholas S, Lipkowitz S. 108.  2010. The N terminus of Cbl-c regulates ubiquitin ligase activity by modulating affinity for the ubiquitin-conjugating enzyme. J. Biol. Chem. 285:23687–98 [Google Scholar]
  109. Dou H, Buetow L, Hock A, Sibbet GJ, Vousden KH, Huang DT. 109.  2012. Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl. Nat. Struct. Mol. Biol. 19:184–92 [Google Scholar]
  110. Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D. 110.  1999. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. PNAS 96:14973–77 [Google Scholar]
  111. Debonneville C, Flores SY, Kamynina E, Plant PJ, Tauxe C. 111.  et al. 2001. Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na+ channel cell surface expression. EMBO J 20:7052–59 [Google Scholar]
  112. Zhang S, Chang L, Alfieri C, Zhang Z, Yang J. 112.  et al. 2016. Molecular mechanism of APC/C activation by mitotic phosphorylation. Nature 533:260–64 [Google Scholar]
  113. Fujimitsu K, Grimaldi M, Yamano H. 113.  2016. Cyclin-dependent kinase 1-dependent activation of APC/C ubiquitin ligase. Science 352:1121–24 [Google Scholar]
  114. Yamoah K, Oashi T, Sarikas A, Gazdoiu S, Osman R, Pan ZQ. 114.  2008. Autoinhibitory regulation of SCF-mediated ubiquitination by human cullin 1’s C-terminal tail. PNAS 105:12230–35 [Google Scholar]
  115. Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA. 115.  2008. Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell 134:995–1006 [Google Scholar]
  116. Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N. 116.  2006. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 443:590–93 [Google Scholar]
  117. Cui J, Yao Q, Li S, Ding X, Lu Q. 117.  et al. 2010. Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family. Science 329:1215–18 [Google Scholar]
  118. Yu C, Mao H, Novitsky EJ, Tang X, Rychnovsky SD. 118.  et al. 2015. Gln40 deamidation blocks structural reconfiguration and activation of SCF ubiquitin ligase complex by Nedd8. Nat. Commun. 6:10053 [Google Scholar]
  119. Jubelin G, Taieb F, Duda DM, Hsu Y, Samba-Louaka A. 119.  et al. 2010. Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways. PLOS Pathog 6:e1001128 [Google Scholar]
  120. Boh BK, Ng MY, Leck YC, Shaw B, Long J. 120.  et al. 2011. Inhibition of cullin RING ligases by cycle inhibiting factor: evidence for interference with Nedd8-induced conformational control. J. Mol. Biol. 413:430–37 [Google Scholar]
  121. de Bie P, Ciechanover A. 121.  2011. Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms. Cell Death Differ 18:1393–402 [Google Scholar]
  122. Ranaweera RS, Yang X. 122.  2013. Auto-ubiquitination of Mdm2 enhances its substrate ubiquitin ligase activity. J. Biol. Chem. 288:18939–46 [Google Scholar]
  123. Ben-Saadon R, Zaaroor D, Ziv T, Ciechanover A. 123.  2006. The polycomb protein Ring1B generates self atypical mixed ubiquitin chains required for its in vitro histone H2A ligase activity. Mol. Cell 24:701–11 [Google Scholar]
  124. Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D. 124.  2008. Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain. Biochem. J. 415:155–63 [Google Scholar]
  125. Baldridge RD, Rapoport TA. 125.  2016. Autoubiquitination of the Hrd1 ligase triggers protein retrotranslocation in ERAD. Cell 166:394–407 [Google Scholar]
  126. Pellegrino S, Altmeyer M. 126.  2016. Interplay between ubiquitin, SUMO, and poly(ADP-ribose) in the cellular response to genotoxic stress. Front. Genet. 7:63 [Google Scholar]
  127. Teloni F, Altmeyer M. 127.  2016. Readers of poly(ADP-ribose): designed to be fit for purpose. Nucleic Acids Res 44:993–1006 [Google Scholar]
  128. Zhang Y, Liu S, Mickanin C, Feng Y, Charlat O. 128.  et al. 2011. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat. Cell Biol. 13:623–29 [Google Scholar]
  129. Li M, Yu X. 129.  2013. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell 23:693–704 [Google Scholar]
  130. Wang Z, Michaud GA, Cheng Z, Zhang Y, Hinds TR. 130.  et al. 2012. Recognition of the iso-ADP-ribose moiety in poly(ADP-ribose) by WWE domains suggests a general mechanism for poly(ADP-ribosyl)ation-dependent ubiquitination. Genes Dev 26:235–40 [Google Scholar]
  131. DaRosa PA, Wang Z, Jiang X, Pruneda JN, Cong F. 131.  et al. 2015. Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal. Nature 517:223–26 [Google Scholar]
  132. Ravid T, Hochstrasser M. 132.  2008. Diversity of degradation signals in the ubiquitin-proteasome system. Nat. Rev. Mol. Cell Biol. 9:679–90 [Google Scholar]
  133. Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP. 133.  2003. Structure of a β-TrCP1-Skp1-β-catenin complex: destruction motif binding and lysine specificity of the SCFβ-TrCP1 ubiquitin ligase. Mol. Cell 11:1445–56 [Google Scholar]
  134. Min JH, Yang H, Ivan M, Gertler F, Kaelin WG, Pavletich NP. 134.  2002. Structure of an HIF-1α–pVHL complex: hydroxyproline recognition in signaling. Science 296:1886–89 [Google Scholar]
  135. Hao B, Oehlmann S, Sowa ME, Harper JW, Pavletich NP. 135.  2007. Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases. Mol. Cell 26:131–43 [Google Scholar]
  136. Hao B, Zheng N, Schulman BA, Wu G, Miller JJ. 136.  et al. 2005. Structural basis of the Cks1-dependent recognition of p27Kip1 by the SCFSkp2 ubiquitin ligase. Mol. Cell 20:9–19 [Google Scholar]
  137. Tang X, Orlicky S, Lin Z, Willems A, Neculai D. 137.  et al. 2007. Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination. Cell 129:1165–76 [Google Scholar]
  138. Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ. 138.  1999. Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature 398:84–90 [Google Scholar]
  139. Muñoz-Escobar J, Matta-Camacho E, Kozlov G, Gehring K. 139.  2015. The MLLE domain of the ubiquitin ligase UBR5 binds to its catalytic domain to regulate substrate binding. J. Biol. Chem. 290:22841–50 [Google Scholar]
  140. Kanelis V, Rotin D, Forman-Kay JD. 140.  2001. Solution structure of a Nedd4 WW domain-ENaC peptide complex. Nat. Struct. Biol. 8:407–12 [Google Scholar]
  141. Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M. 141.  et al. 2006. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol. Cell 21:689–700 [Google Scholar]
  142. Lo SC, Li X, Henzl MT, Beamer LJ, Hannink M. 142.  2006. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J 25:3605–17 [Google Scholar]
  143. Fukutomi T, Takagi K, Mizushima T, Ohuchi N, Yamamoto M. 143.  2014. Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. Mol. Cell. Biol. 34:832–46 [Google Scholar]
  144. Schumacher FR, Sorrell FJ, Alessi DR, Bullock AN, Kurz T. 144.  2014. Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation. Biochem. J. 460:237–46 [Google Scholar]
  145. Jin L, Pahuja KB, Wickliffe KE, Gorur A, Baumgärtel C. 145.  et al. 2012. Ubiquitin-dependent regulation of COPII coat size and function. Nature 482:495–500 [Google Scholar]
  146. Suzuki T, Yamamoto M. 146.  2015. Molecular basis of the Keap1-Nrf2 system. Free Radic. Biol. Med. 88:93–100 [Google Scholar]
  147. Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J. 147.  et al. 2013. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol. Cell 51:618–31 [Google Scholar]
  148. Li Y, Wu H, Wu W, Zhuo W, Liu W. 148.  et al. 2014. Structural insights into the TRIM family of ubiquitin E3 ligases. Cell Res 24:762–65 [Google Scholar]
  149. Ogura T, Tong KI, Mio K, Maruyama Y, Kurokawa H. 149.  et al. 2010. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. PNAS 107:2842–47 [Google Scholar]
  150. Zhuang M, Calabrese MF, Liu J, Waddell MB, Nourse A. 150.  et al. 2009. Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Mol. Cell 36:39–50 [Google Scholar]
  151. Welcker M, Larimore EA, Swanger J, Bengoechea-Alonso MT, Grim JE. 151.  et al. 2013. Fbw7 dimerization determines the specificity and robustness of substrate degradation. Genes Dev 27:2531–36 [Google Scholar]
  152. Tian W, Li B, Warrington R, Tomchick DR, Yu H, Luo X. 152.  2012. Structural analysis of human Cdc20 supports multisite degron recognition by APC/C. PNAS 109:18419–24 [Google Scholar]
  153. He J, Chao WC, Zhang Z, Yang J, Cronin N, Barford D. 153.  2013. Insights into degron recognition by APC/C coactivators from the structure of an Acm1-Cdh1 complex. Mol. Cell 50:649–60 [Google Scholar]
  154. McMillan BJ, Schnute B, Ohlenhard N, Zimmerman B, Miles L. 154.  et al. 2015. A tail of two sites: a bipartite mechanism for recognition of notch ligands by mind bomb E3 ligases. Mol. Cell 57:912–24 [Google Scholar]
  155. Choi WS, Jeong BC, Joo YJ, Lee MR, Kim J. 155.  et al. 2010. Structural basis for the recognition of N-end rule substrates by the UBR box of ubiquitin ligases. Nat. Struct. Mol. Biol. 17:1175–81 [Google Scholar]
  156. Matta-Camacho E, Kozlov G, Li FF, Gehring K. 156.  2010. Structural basis of substrate recognition and specificity in the N-end rule pathway. Nat. Struct. Mol. Biol. 17:1182–87 [Google Scholar]
  157. Piatkov KI, Colnaghi L, Békés M, Varshavsky A, Huang TT. 157.  2012. The auto-generated fragment of the Usp1 deubiquitylase is a physiological substrate of the N-end rule pathway. Mol. Cell 48:926–33 [Google Scholar]
  158. Lin HC, Ho SC, Chen YY, Khoo KH, Hsu PH, Yen HC. 158.  2015. CRL2 aids elimination of truncated selenoproteins produced by failed UGA/Sec decoding. Science 349:91–95 [Google Scholar]
  159. Rosenbaum JC, Fredrickson EK, Oeser ML, Garrett-Engele CM, Locke MN. 159.  et al. 2011. Disorder targets misorder in nuclear quality control degradation: A disordered ubiquitin ligase directly recognizes its misfolded substrates. Mol. Cell 41:93–106 [Google Scholar]
  160. Mizushima T, Hirao T, Yoshida Y, Lee SJ, Chiba T. 160.  et al. 2004. Structural basis of sugar-recognizing ubiquitin ligase. Nat. Struct. Mol. Biol. 11:365–70 [Google Scholar]
  161. Zeng Z, Wang W, Yang Y, Chen Y, Yang X. 161.  et al. 2010. Structural basis of selective ubiquitination of TRF1 by SCFFbx4. Dev. Cell 18:214–25 [Google Scholar]
  162. Chang W, Dynek JN, Smith S. 162.  2003. TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev 17:1328–33 [Google Scholar]
  163. Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH. 163.  et al. 2013. SCFFBXL3 ubiquitin ligase targets cryptochromes at their cofactor pocket. Nature 496:64–68 [Google Scholar]
  164. Partch CL, Green CB, Takahashi JS. 164.  2014. Molecular architecture of the mammalian circadian clock. Trends Cell Biol 24:90–99 [Google Scholar]
  165. Shirogane T, Jin J, Ang XL, Harper JW. 165.  2005. SCFβ-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein. J. Biol. Chem. 280:26863–72 [Google Scholar]
  166. Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM. 166.  et al. 2007. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316:900–4 [Google Scholar]
  167. Nangle S, Xing W, Zheng N. 167.  2013. Crystal structure of mammalian cryptochrome in complex with a small molecule competitor of its ubiquitin ligase. Cell Res 23:1417–19 [Google Scholar]
  168. Schmalen I, Reischl S, Wallach T, Klemz R, Grudziecki A. 168.  et al. 2014. Interaction of circadian clock proteins CRY1 and PER2 is modulated by zinc binding and disulfide bond formation. Cell 157:1203–15 [Google Scholar]
  169. Cao J, Yan Q. 169.  2012. Histone ubiquitination and deubiquitination in transcription, DNA damage response, and cancer. Front. Oncol. 2:26 [Google Scholar]
  170. McGinty RK, Henrici RC, Tan S. 170.  2014. Crystal structure of the PRC1 ubiquitylation module bound to the nucleosome. Nature 514:591–96 [Google Scholar]
  171. Buchwald G, van der Stoop P, Weichenrieder O, Perrakis A, van Lohuizen M, Sixma TK. 171.  2006. Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins Bmi1 and Ring1b. EMBO J 25:2465–74 [Google Scholar]
  172. Isaacson MK, Ploegh HL. 172.  2009. Ubiquitination, ubiquitin-like modifiers, and deubiquitination in viral infection. Cell Host Microbe 5:559–70 [Google Scholar]
  173. Smith MC, Boutell C, Davido DJ. 173.  2011. HSV-1 ICP0: paving the way for viral replication. Future Virol 6:421–29 [Google Scholar]
  174. Chaurushiya MS, Lilley CE, Aslanian A, Meisenhelder J, Scott DC. 174.  et al. 2012. Viral E3 ubiquitin ligase-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain. Mol. Cell 46:79–90 [Google Scholar]
  175. Scheffner M, Nuber U, Huibregtse JM. 175.  1995. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature 373:81–83 [Google Scholar]
  176. Martinez-Zapien D, Ruiz FX, Poirson J, Mitschler A, Ramirez J. 176.  et al. 2016. Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 529:541–45 [Google Scholar]
  177. Simon V, Bloch N, Landau NR. 177.  2015. Intrinsic host restrictions to HIV-1 and mechanisms of viral escape. Nat. Immunol. 16:546–53 [Google Scholar]
  178. Yu X, Yu Y, Liu B, Luo K, Kong W. 178.  et al. 2003. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science 302:1056–60 [Google Scholar]
  179. Guo Y, Dong L, Qiu X, Wang Y, Zhang B. 179.  et al. 2014. Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif. Nature 505:229–33 [Google Scholar]
  180. Letko M, Booiman T, Kootstra N, Simon V, Ooms M. 180.  2015. Identification of the HIV-1 Vif and human APOBEC3G protein interface. Cell Rep 13:1789–99 [Google Scholar]
  181. Schwefel D, Groom HC, Boucherit VC, Christodoulou E, Walker PA. 181.  et al. 2014. Structural basis of lentiviral subversion of a cellular protein degradation pathway. Nature 505:234–38 [Google Scholar]
  182. Li T, Robert EI, van Breugel PC, Strubin M, Zheng N. 182.  2010. A promiscuous α-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery. Nat. Struct. Mol. Biol. 17:105–11 [Google Scholar]
  183. Li T, Chen X, Garbutt KC, Zhou P, Zheng N. 183.  2006. Structure of DDB1 in complex with a paramyxovirus V protein: viral hijack of a propeller cluster in ubiquitin ligase. Cell 124:105–17 [Google Scholar]
  184. Decorsière A, Mueller H, van Breugel PC, Abdul F, Gerossier L. 184.  et al. 2016. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature 531:386–89 [Google Scholar]
  185. Precious B, Childs K, Fitzpatrick-Swallow V, Goodbourn S, Randall RE. 185.  2005. Simian virus 5 V protein acts as an adaptor, linking DDB1 to STAT2, to facilitate the ubiquitination of STAT1. J. Virol. 79:13434–41 [Google Scholar]
  186. Welcker M, Clurman BE. 186.  2005. The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4. J. Biol. Chem. 280:7654–58 [Google Scholar]
  187. Bergametti F, Sitterlin D, Transy C. 187.  2002. Turnover of hepatitis B virus X protein is regulated by damaged DNA-binding complex. J. Virol. 76:6495–501 [Google Scholar]
  188. Shabek N, Zheng N. 188.  2014. Plant ubiquitin ligases as signaling hubs. Nat. Struct. Mol. Biol. 21:293–96 [Google Scholar]
  189. Dharmasiri N, Dharmasiri S, Estelle M. 189.  2005. The F-box protein TIR1 is an auxin receptor. Nature 435:441–45 [Google Scholar]
  190. Kepinski S, Leyser O. 190.  2005. The Arabidopsis F-box protein TIR1 is an auxin receptor. Nature 435:446–51 [Google Scholar]
  191. Calderon-Villalobos LI, Tan X, Zheng N, Estelle M. 191.  2010. Auxin perception—structural insights. Cold Spring Harb. Perspect. Biol. 2:a005546 [Google Scholar]
  192. Tan X, Calderon-Villalobos LI, Sharon M, Zheng C, Robinson CV. 192.  et al. 2007. Mechanism of auxin perception by the TIR1 ubiquitin ligase. Nature 446:640–45 [Google Scholar]
  193. Sheard LB, Tan X, Mao H, Withers J, Ben-Nissan G. 193.  et al. 2010. Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ co-receptor. Nature 468:400–5 [Google Scholar]
  194. Murase K, Hirano Y, Sun TP, Hakoshima T. 194.  2008. Gibberellin-induced DELLA recognition by the gibberellin receptor GID1. Nature 456:459–63 [Google Scholar]
  195. Shimada A, Ueguchi-Tanaka M, Nakatsu T, Nakajima M, Naoe Y. 195.  et al. 2008. Structural basis for gibberellin recognition by its receptor GID1. Nature 456:520–23 [Google Scholar]
  196. Laha D, Johnen P, Azevedo C, Dynowski M, Weiß M. 196.  et al. 2015. VIH2 regulates the synthesis of inositol pyrophosphate InsP8 and jasmonate-dependent defenses in Arabidopsis. Plant Cell 27:1082–97 [Google Scholar]
  197. Wild R, Gerasimaite R, Jung JY, Truffault V, Pavlovic I. 197.  et al. 2016. Control of eukaryotic phosphate homeostasis by inositol polyphosphate sensor domains. Science 352:986–90 [Google Scholar]
  198. Ruiz JC, Bruick RK. 198.  2014. F-box and leucine-rich repeat protein 5 (FBXL5): sensing intracellular iron and oxygen. J. Inorg. Biochem. 133:73–77 [Google Scholar]
  199. Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM. 199.  et al. 2010. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465:1084–88 [Google Scholar]
  200. Dueber EC, Schoeffler AJ, Lingel A, Elliott JM, Fedorova AV. 200.  et al. 2011. Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science 334:376–80 [Google Scholar]
  201. Aghajan M, Jonai N, Flick K, Fu F, Luo M. 201.  et al. 2010. Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase. Nat. Biotechnol. 28:738–42 [Google Scholar]
  202. Orlicky S, Tang X, Neduva V, Elowe N, Brown ED. 202.  et al. 2010. An allosteric inhibitor of substrate recognition by the SCFCdc4 ubiquitin ligase. Nat. Biotechnol. 28:733–37 [Google Scholar]
  203. Chan CH, Morrow JK, Li CF, Gao Y, Jin G. 203.  et al. 2013. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell 154:556–68 [Google Scholar]
  204. Wu L, Grigoryan AV, Li Y, Hao B, Pagano M, Cardozo TJ. 204.  2012. Specific small molecule inhibitors of Skp2-mediated p27 degradation. Chem. Biol. 19:1515–24 [Google Scholar]
  205. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. 205.  2001. Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. PNAS 98:8554–59 [Google Scholar]
  206. Ito T, Ando H, Suzuki T, Ogura T, Hotta K. 206.  et al. 2010. Identification of a primary target of thalidomide teratogenicity. Science 327:1345–50 [Google Scholar]
  207. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ. 207.  et al. 2014. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–9 [Google Scholar]
  208. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN. 208.  et al. 2014. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–5 [Google Scholar]
  209. Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN. 209.  et al. 2015. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523:183–88 [Google Scholar]
  210. Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC. 210.  et al. 2016. A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature 535:252–57 [Google Scholar]
  211. Petzold G, Fischer ES, Thomä NH. 211.  2016. Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature 532:127–30 [Google Scholar]
  212. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A. 212.  et al. 2015. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348:1376–81 [Google Scholar]
  213. Lu J, Qian Y, Altieri M, Dong H, Wang J. 213.  et al. 2015. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22:755–63 [Google Scholar]
/content/journals/10.1146/annurev-biochem-060815-014922
Loading
/content/journals/10.1146/annurev-biochem-060815-014922
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error