1932

Abstract

Cullin-RING ubiquitin ligases (CRLs) are dynamic modular platforms that regulate myriad biological processes through target-specific ubiquitylation. Our knowledge of this system emerged from the F-box hypothesis, posited a quarter century ago: Numerous interchangeable F-box proteins confer specific substrate recognition for a core CUL1-based RING E3 ubiquitin ligase. This paradigm has been expanded through the evolution of a superfamily of analogous modular CRLs, with five major families and over 200 different substrate-binding receptors in humans. Regulation is achieved by numerous factors organized in circuits that dynamically control CRL activation and substrate ubiquitylation. CRLs also serve as a vast landscape for developing small molecules that reshape interactions and promote targeted ubiquitylation-dependent turnover of proteins of interest. Here, we review molecular principles underlying CRL function, the role of allosteric and conformational mechanisms in controlling substrate timing and ubiquitylation, and how the dynamics of substrate receptor interchange drives the turnover of selected target proteins to promote cellular decision-making.

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2021-06-20
2024-06-19
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Literature Cited

  1. 1. 
    Bai C, Sen P, Hofmann K, Ma L, Goebl M et al. 1996. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86:263–74
    [Google Scholar]
  2. 2. 
    Schwob E, Bohm T, Mendenhall MD, Nasmyth K 1994. The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae. Cell 79:233–44
    [Google Scholar]
  3. 3. 
    Mathias N, Johnson SL, Winey M, Adams AE, Goetsch L et al. 1996. Cdc53p acts in concert with Cdc4p and Cdc34p to control the G1-to-S-phase transition and identifies a conserved family of proteins. Mol. Cell. Biol. 16:6634–43
    [Google Scholar]
  4. 4. 
    Willems AR, Lanker S, Patton EE, Craig KL, Nason TF et al. 1996. Cdc53 targets phosphorylated G1 cyclins for degradation by the ubiquitin proteolytic pathway. Cell 86:453–63
    [Google Scholar]
  5. 5. 
    Feldman RM, Correll CC, Kaplan KB, Deshaies RJ. 1997. A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 91:221–30
    [Google Scholar]
  6. 6. 
    Skowyra D, Craig KL, Tyers M, Elledge SJ, Harper JW. 1997. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91:209–19
    [Google Scholar]
  7. 7. 
    Verma R, Feldman RM, Deshaies RJ. 1997. SIC1 is ubiquitinated in vitro by a pathway that requires CDC4, CDC34, and cyclin/CDK activities. Mol. Biol. Cell 8:1427–37
    [Google Scholar]
  8. 8. 
    Patton EE, Willems AR, Sa D, Kuras L, Thomas D et al. 1998. Cdc53 is a scaffold protein for multiple Cdc34/Skp1/F-box protein complexes that regulate cell division and methionine biosynthesis in yeast. Genes Dev 12:692–705
    [Google Scholar]
  9. 9. 
    Li FN, Johnston M. 1997. Grr1 of Saccharomyces cerevisiae is connected to the ubiquitin proteolysis machinery through Skp1: coupling glucose sensing to gene expression and the cell cycle. EMBO J 16:5629–38
    [Google Scholar]
  10. 10. 
    Kipreos ET, Lander LE, Wing JP, He WW, Hedgecock EM. 1996. cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family. Cell 85:829–39
    [Google Scholar]
  11. 11. 
    Bennett EJ, Rush J, Gygi SP, Harper JW. 2010. Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 143:951–65
    [Google Scholar]
  12. 12. 
    Kamura T, Sato S, Haque D, Liu L, Kaelin WG Jr. et al. 1998. The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev 12:3872–81
    [Google Scholar]
  13. 13. 
    Xu L, Wei Y, Reboul J, Vaglio P, Shin TH et al. 2003. BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature 425:316–21
    [Google Scholar]
  14. 14. 
    Pintard L, Willis JH, Willems A, Johnson JL, Srayko M et al. 2003. The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature 425:311–16
    [Google Scholar]
  15. 15. 
    Geyer R, Wee S, Anderson S, Yates J, Wolf DA. 2003. BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases. Mol. Cell 12:783–90
    [Google Scholar]
  16. 16. 
    Furukawa M, He YJ, Borchers C, Xiong Y. 2003. Targeting of protein ubiquitylation by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat. Cell Biol. 5:1001–7
    [Google Scholar]
  17. 17. 
    Zhuang M, Calabrese MF, Liu J, Waddell MB, Nourse A et al. 2009. Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Mol. Cell 36:39–50
    [Google Scholar]
  18. 18. 
    Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N. 2006. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 443:590–93
    [Google Scholar]
  19. 19. 
    Jin J, Arias EE, Chen J, Harper JW, Walter JC. 2006. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol. Cell 23:709–21
    [Google Scholar]
  20. 20. 
    He YJ, McCall CM, Hu J, Zeng Y, Xiong Y. 2006. DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases. Genes Dev 20:2949–54
    [Google Scholar]
  21. 21. 
    Higa LA, Wu M, Ye T, Kobayashi R, Sun H, Zhang H. 2006. CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nat. Cell Biol. 8:1277–83
    [Google Scholar]
  22. 22. 
    Ohta T, Michel JJ, Schottelius AJ, Xiong Y. 1999. ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol. Cell 3:535–41
    [Google Scholar]
  23. 23. 
    Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ et al. 1999. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 284:657–61
    [Google Scholar]
  24. 24. 
    Seol JH, Feldman RM, Zachariae W, Shevchenko A, Correll CC et al. 1999. Cdc53/cullin and the essential Hrt1 RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34. Genes Dev 13:1614–26
    [Google Scholar]
  25. 25. 
    Skowyra D, Koepp DM, Kamura T, Conrad MN, Conaway RC et al. 1999. Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1. Science 284:662–65
    [Google Scholar]
  26. 26. 
    Tan P, Fuchs SY, Chen A, Wu K, Gomez C et al. 1999. Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of IκBα. Mol. Cell 3:527–33
    [Google Scholar]
  27. 27. 
    Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC. 1999. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science 286:309–12
    [Google Scholar]
  28. 28. 
    Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM 1999. RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. PNAS 96:11364–69
    [Google Scholar]
  29. 29. 
    Scott DC, Rhee DY, Duda DM, Kelsall IR, Olszewski JL et al. 2016. Two distinct types of E3 ligases work in unison to regulate substrate ubiquitylation. Cell 166:1198–214.e24
    [Google Scholar]
  30. 30. 
    Liu J, Furukawa M, Matsumoto T, Xiong Y. 2002. NEDD8 modification of CUL1 dissociates p120CAND1, an inhibitor of CUL1-SKP1 binding and SCF ligases. Mol. Cell 10:1511–18
    [Google Scholar]
  31. 31. 
    Zheng J, Yang X, Harrell JM, Ryzhikov S, Shim EH et al. 2002. CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Mol. Cell 10:1519–26
    [Google Scholar]
  32. 32. 
    Goldenberg SJ, Cascio TC, Shumway SD, Garbutt KC, Liu J et al. 2004. Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubiquitin ligases. Cell 119:517–28
    [Google Scholar]
  33. 33. 
    Pierce NW, Lee JE, Liu X, Sweredoski MJ, Graham RL et al. 2013. Cand1 promotes assembly of new SCF complexes through dynamic exchange of F box proteins. Cell 153:206–15
    [Google Scholar]
  34. 34. 
    Zemla A, Thomas Y, Kedziora S, Knebel A, Wood NT et al. 2013. CSN- and CAND1-dependent remodelling of the budding yeast SCF complex. Nat. Commun. 4:1641
    [Google Scholar]
  35. 35. 
    Wu S, Zhu W, Nhan T, Toth JI, Petroski MD, Wolf DA. 2013. CAND1 controls in vivo dynamics of the cullin 1-RING ubiquitin ligase repertoire. Nat. Commun. 4:1642
    [Google Scholar]
  36. 36. 
    Scott DC, Sviderskiy VO, Monda JK, Lydeard JR, Cho SE 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]
  37. 37. 
    Liu X, Reitsma JM, Mamrosh JL, Zhang Y, Straube R, Deshaies RJ. 2018. Cand1-mediated adaptive exchange mechanism enables variation in F-box protein expression. Mol. Cell 69:773–86.e6
    [Google Scholar]
  38. 38. 
    Reitsma JM, Liu X, Reichermeier KM, Moradian A, Sweredoski MJ et al. 2017. Composition and regulation of the cellular repertoire of SCF ubiquitin ligases. Cell 171:1326–39.e14
    [Google Scholar]
  39. 39. 
    Reichermeier KM, Straube R, Reitsma JM, Sweredoski MJ, Rose CM et al. 2020. PIKES analysis reveals response to degraders and key regulatory mechanisms of the CRL4 network. Mol. Cell 77:1092–106.e9
    [Google Scholar]
  40. 40. 
    Enchev RI, Scott DC, da Fonseca PC, Schreiber A, Monda JK et al. 2012. Structural basis for a reciprocal regulation between SCF and CSN. Cell Rep 2:616–27
    [Google Scholar]
  41. 41. 
    Mosadeghi R, Reichermeier KM, Winkler M, Schreiber A, Reitsma JM et al. 2016. Structural and kinetic analysis of the COP9-Signalosome activation and the cullin-RING ubiquitin ligase deneddylation cycle. eLife 5:e12102
    [Google Scholar]
  42. 42. 
    Cavadini S, Fischer ES, Bunker RD, Potenza A, Lingaraju GM et al. 2016. Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome. Nature 531:598–603
    [Google Scholar]
  43. 43. 
    Bornstein G, Ganoth D, Hershko A 2006. Regulation of neddylation and deneddylation of cullin1 in SCFSkp2 ubiquitin ligase by F-box protein and substrate. PNAS 103:11515–20
    [Google Scholar]
  44. 44. 
    Chew EH, Hagen T. 2007. Substrate-mediated regulation of cullin neddylation. J. Biol. Chem. 282:17032–40
    [Google Scholar]
  45. 45. 
    Fischer ES, Scrima A, Bohm K, Matsumoto S, Lingaraju GM et al. 2011. The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation. Cell 147:1024–39
    [Google Scholar]
  46. 46. 
    Emberley ED, Mosadeghi R, Deshaies RJ. 2012. Deconjugation of Nedd8 from Cul1 is directly regulated by Skp1-F-box and substrate, and the COP9 signalosome inhibits deneddylated SCF by a noncatalytic mechanism. J. Biol. Chem. 287:29679–89
    [Google Scholar]
  47. 47. 
    Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD et al. 2002. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 416:703–9
    [Google Scholar]
  48. 48. 
    Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA. 2008. Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell 134:995–1006
    [Google Scholar]
  49. 49. 
    Baek K, Krist DT, Prabu JR, Hill S, Klugel M et al. 2020. NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly. Nature 578:461–66
    [Google Scholar]
  50. 50. 
    Yamoah K, Oashi T, Sarikas A, Gazdoiu S, Osman R, Pan ZQ 2008. Autoinhibitory regulation of SCF-mediated ubiquitination by human cullin 1’s C-terminal tail. PNAS 105:12230–35
    [Google Scholar]
  51. 51. 
    Saha A, Deshaies RJ. 2008. Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation. Mol. Cell 32:21–31
    [Google Scholar]
  52. 52. 
    Yu C, Mao H, Novitsky EJ, Tang X, Rychnovsky SD et al. 2015. Gln40 deamidation blocks structural reconfiguration and activation of SCF ubiquitin ligase complex by Nedd8. Nat. Commun. 6:10053
    [Google Scholar]
  53. 53. 
    Stebbins CE, Kaelin WG Jr., Pavletich NP. 1999. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284:455–61
    [Google Scholar]
  54. 54. 
    Schulman BA, Carrano AC, Jeffrey PD, Bowen Z, Kinnucan ER et al. 2000. Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex. Nature 408:381–86
    [Google Scholar]
  55. 55. 
    Kamura T, Maenaka K, Kotoshiba S, Matsumoto M, Kohda D et al. 2004. VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes Dev 18:3055–65
    [Google Scholar]
  56. 56. 
    Shabek N, Ruble J, Waston CJ, Garbutt KC, Hinds TR et al. 2018. Structural insights into DDA1 function as a core component of the CRL4-DDB1 ubiquitin ligase. Cell Discov 4:67
    [Google Scholar]
  57. 57. 
    Orlicky S, Tang X, Willems A, Tyers M, Sicheri F. 2003. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell 112:243–56
    [Google Scholar]
  58. 58. 
    Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP. 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]
  59. 59. 
    Babon JJ, McManus EJ, Yao S, DeSouza DP, Mielke LA et al. 2006. The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability. Mol. Cell 22:205–16
    [Google Scholar]
  60. 60. 
    Hao B, Oehlmann S, Sowa ME, Harper JW, Pavletich NP. 2007. Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases. Mol. Cell 26:131–43
    [Google Scholar]
  61. 61. 
    Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M et al. 2001. The cell-cycle regulatory protein Cks1 is required for SCFSkp2-mediated ubiquitinylation of p27. Nat. Cell Biol. 3:321–24
    [Google Scholar]
  62. 62. 
    Hao B, Zheng N, Schulman BA, Wu G, Miller JJ et al. 2005. Structural basis of the Cks1-dependent recognition of p27Kip1 by the SCFSkp2 ubiquitin ligase. Mol. Cell 20:9–19
    [Google Scholar]
  63. 63. 
    Frescas D, Pagano M. 2008. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nat. Rev. Cancer 8:438–49
    [Google Scholar]
  64. 64. 
    Fiol CJ, Wang A, Roeske RW, Roach PJ. 1990. Ordered multisite protein phosphorylation. Analysis of glycogen synthase kinase 3 action using model peptide substrates. J. Biol. Chem. 265:6061–65
    [Google Scholar]
  65. 65. 
    Zhang Q, Shi Q, Chen Y, Yue T, Li S et al. 2009. Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase. PNAS 106:21191–96
    [Google Scholar]
  66. 66. 
    Tang X, Orlicky S, Lin Z, Willems A, Neculai D et al. 2007. Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination. Cell 129:1165–76
    [Google Scholar]
  67. 67. 
    Welcker M, Larimore EA, Swanger J, Bengoechea-Alonso MT, Grim JE et al. 2013. Fbw7 dimerization determines the specificity and robustness of substrate degradation. Genes Dev 27:2531–36
    [Google Scholar]
  68. 68. 
    Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M. 2006. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol. Cell. Biol. 26:2887–900
    [Google Scholar]
  69. 69. 
    Ivan M, Kondo K, Yang H, Kim W, Valiando J et al. 2001. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–68
    [Google Scholar]
  70. 70. 
    Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J et al. 2001. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–72
    [Google Scholar]
  71. 71. 
    Yu F, White SB, Zhao Q, Lee FS 2001. HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. PNAS 98:9630–35
    [Google Scholar]
  72. 72. 
    Yoshida Y, Chiba T, Tokunaga F, Kawasaki H, Iwai K et al. 2002. E3 ubiquitin ligase that recognizes sugar chains. Nature 418:438–42
    [Google Scholar]
  73. 73. 
    Nguyen TV, Lee JE, Sweredoski MJ, Yang SJ, Jeon SJ et al. 2016. Glutamine triggers acetylation-dependent degradation of glutamine synthetase via the thalidomide receptor cereblon. Mol. Cell 61:809–20
    [Google Scholar]
  74. 74. 
    Koren I, Timms RT, Kula T, Xu Q, Li MZ, Elledge SJ. 2018. The eukaryotic proteome is shaped by E3 ubiquitin ligases targeting C-terminal degrons. Cell 173:1622–35.e14
    [Google Scholar]
  75. 75. 
    Lin HC, Yeh CW, Chen YF, Lee TT, Hsieh PY et al. 2018. C-terminal end-directed protein elimination by CRL2 ubiquitin ligases. Mol. Cell 70:602–13.e3
    [Google Scholar]
  76. 76. 
    Timms RT, Zhang Z, Rhee DY, Harper JW, Koren I, Elledge SJ 2019. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science 365:eaaw4912
    [Google Scholar]
  77. 77. 
    Rusnac DV, Lin HC, Canzani D, Tien KX, Hinds TR et al. 2018. Recognition of the diglycine C-end degron by CRL2KLHDC2 ubiquitin ligase. Mol. Cell 72:813–22.e4
    [Google Scholar]
  78. 78. 
    Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y et al. 2004. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol. 24:7130–39
    [Google Scholar]
  79. 79. 
    Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M. 2004. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol. Cell. Biol. 24:10941–53
    [Google Scholar]
  80. 80. 
    Furukawa M, Xiong Y. 2005. BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol. Cell. Biol. 25:162–71
    [Google Scholar]
  81. 81. 
    Mena EL, Jevtic P, Greber BJ, Gee CL, Lew BG et al. 2020. Structural basis for dimerization quality control. Nature 586:452–56
    [Google Scholar]
  82. 82. 
    Mena EL, Kjolby RAS, Saxton RA, Werner A, Lew BG et al. 2018. Dimerization quality control ensures neuronal development and survival. Science 362:eaap8236
    [Google Scholar]
  83. 83. 
    Vashisht AA, Zumbrennen KB, Huang X, Powers DN, Durazo A et al. 2009. Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science 326:718–21
    [Google Scholar]
  84. 84. 
    Salahudeen AA, Thompson JW, Ruiz JC, Ma HW, Kinch LN et al. 2009. An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science 326:722–26
    [Google Scholar]
  85. 85. 
    Wang H, Shi H, Rajan M, Canarie ER, Hong S et al. 2020. FBXL5 regulates IRP2 stability in iron homeostasis via an oxygen-responsive [2Fe2S] cluster. Mol. Cell 78:31–41.e5
    [Google Scholar]
  86. 86. 
    Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH et al. 2013. SCFFBXL3 ubiquitin ligase targets cryptochromes at their cofactor pocket. Nature 496:64–68
    [Google Scholar]
  87. 87. 
    Yu X, Yu Y, Liu B, Luo K, Kong W et al. 2003. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science 302:1056–60
    [Google Scholar]
  88. 88. 
    Li T, Chen X, Garbutt KC, Zhou P, Zheng N. 2006. Structure of DDB1 in complex with a paramyxo-virus V protein: viral hijack of a propeller cluster in ubiquitin ligase. Cell 124:105–17
    [Google Scholar]
  89. 89. 
    Margottin F, Bour SP, Durand H, Selig L, Benichou S et al. 1998. A novel human WD protein, h-βTrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol. Cell 1:565–74
    [Google Scholar]
  90. 90. 
    Le Rouzic E, Belaidouni N, Estrabaud E, Morel M, Rain JC et al. 2007. HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase. Cell Cycle 6:182–88
    [Google Scholar]
  91. 91. 
    Hua Z, Vierstra RD. 2011. The cullin-RING ubiquitin-protein ligases. Annu. Rev. Plant Biol. 62:299–334
    [Google Scholar]
  92. 92. 
    Dharmasiri N, Dharmasiri S, Estelle M 2005. The F-box protein TIR1 is an auxin receptor. Nature 435:441–45
    [Google Scholar]
  93. 93. 
    Tan X, Calderon-Villalobos LI, Sharon M, Zheng C, Robinson CV et al. 2007. Mechanism of auxin perception by the TIR1 ubiquitin ligase. Nature 446:640–45
    [Google Scholar]
  94. 94. 
    Sheard LB, Tan X, Mao H, Withers J, Ben-Nissan G et al. 2010. Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ co-receptor. Nature 468:400–5
    [Google Scholar]
  95. 95. 
    Murase K, Hirano Y, Sun TP, Hakoshima T. 2008. Gibberellin-induced DELLA recognition by the gibberellin receptor GID1. Nature 456:459–63
    [Google Scholar]
  96. 96. 
    Shimada A, Ueguchi-Tanaka M, Nakatsu T, Nakajima M, Naoe Y et al. 2008. Structural basis for gibberellin recognition by its receptor GID1. Nature 456:520–23
    [Google Scholar]
  97. 97. 
    Shabek N, Ticchiarelli F, Mao H, Hinds TR, Leyser O, Zheng N. 2018. Structural plasticity of D3–D14 ubiquitin ligase in strigolactone signalling. Nature 563:652–56
    [Google Scholar]
  98. 98. 
    Yao R, Ming Z, Yan L, Li S, Wang F et al. 2016. DWARF14 is a non-canonical hormone receptor for strigolactone. Nature 536:469–73
    [Google Scholar]
  99. 99. 
    de Saint Germain A, Clave G, Badet-Denisot MA, Pillot JP, Cornu D et al. 2016. An histidine covalent receptor and butenolide complex mediates strigolactone perception. Nat. Chem. Biol. 12:787–94
    [Google Scholar]
  100. 100. 
    Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ 2001. Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. PNAS 98:8554–59
    [Google Scholar]
  101. 101. 
    Bondeson DP, Mares A, Smith IE, Ko E, Campos S et al. 2015. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11:611–17
    [Google Scholar]
  102. 102. 
    Ito T, Ando H, Suzuki T, Ogura T, Hotta K et al. 2010. Identification of a primary target of thalidomide teratogenicity. Science 327:1345–50
    [Google Scholar]
  103. 103. 
    Lu G, Middleton RE, Sun H, Naniong M, Ott CJ et al. 2014. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–9
    [Google Scholar]
  104. 104. 
    Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN et al. 2014. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–5
    [Google Scholar]
  105. 105. 
    Petzold G, Fischer ES, Thoma NH. 2016. Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature 532:127–30
    [Google Scholar]
  106. 106. 
    Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC et al. 2016. A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature 535:252–57
    [Google Scholar]
  107. 107. 
    Gadd MS, Testa A, Lucas X, Chan KH, Chen W et al. 2017. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13:514–21
    [Google Scholar]
  108. 108. 
    Nowak RP, DeAngelo SL, Buckley D, He Z, Donovan KA et al. 2018. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14:706–14
    [Google Scholar]
  109. 109. 
    Simonetta KR, Taygerly J, Boyle K, Basham SE, Padovani C et al. 2019. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun. 10:1402
    [Google Scholar]
  110. 110. 
    Orlicky S, Tang X, Neduva V, Elowe N, Brown ED et al. 2010. An allosteric inhibitor of substrate recognition by the SCFCdc4 ubiquitin ligase. Nat. Biotechnol. 28:733–37
    [Google Scholar]
  111. 111. 
    Marzahn MR, Marada S, Lee J, Nourse A, Kenrick S et al. 2016. Higher-order oligomerization promotes localization of SPOP to liquid nuclear speckles. EMBO J 35:1254–75
    [Google Scholar]
  112. 112. 
    Bouchard JJ, Otero JH, Scott DC, Szulc E, Martin EW et al. 2018. Cancer mutations of the tumor suppressor SPOP disrupt the formation of active, phase-separated compartments. Mol. Cell 72:19–36.e8
    [Google Scholar]
  113. 113. 
    Kuchay S, Wang H, Marzio A, Jain K, Homer H et al. 2019. GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase. Nat. Struct. Mol. Biol. 26:628–36
    [Google Scholar]
  114. 114. 
    McGourty CA, Akopian D, Walsh C, Gorur A, Werner A et al. 2016. Regulation of the CUL3 ubiquitin ligase by a calcium-dependent co-adaptor. Cell 167:525–38.e14
    [Google Scholar]
  115. 115. 
    Scott DC, Monda JK, Grace CR, Duda DM, Kriwacki RW et al. 2010. A dual E3 mechanism for Rub1 ligation to Cdc53. Mol. Cell 39:784–96
    [Google Scholar]
  116. 116. 
    Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM et al. 2009. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458:732–36
    [Google Scholar]
  117. 117. 
    Wu K, Kovacev J, Pan ZQ. 2010. Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for polyubiquitination on a SCF substrate. Mol. Cell 37:784–96
    [Google Scholar]
  118. 118. 
    Swatek KN, Usher JL, Kueck AF, Gladkova C, Mevissen TET et al. 2019. Insights into ubiquitin chain architecture using Ub-clipping. Nature 572:533–37
    [Google Scholar]
  119. 119. 
    Hill S, Reichermeier K, Scott DC, Samentar L, Coulombe-Huntington J et al. 2019. Robust cullin-RING ligase function is established by a multiplicity of poly-ubiquitylation pathways. eLife 8:e51163
    [Google Scholar]
  120. 120. 
    Yuan WC, Lee YR, Lin SY, Chang LY, Tan YP et al. 2014. K33-linked polyubiquitination of coronin 7 by Cul3-KLHL20 ubiquitin E3 ligase regulates protein trafficking. Mol. Cell 54:586–600
    [Google Scholar]
  121. 121. 
    Liakopoulos D, Doenges G, Matuschewski K, Jentsch S. 1998. A novel protein modification pathway related to the ubiquitin system. EMBO J 17:2208–14
    [Google Scholar]
  122. 122. 
    Lammer D, Mathias N, Laplaza JM, Jiang W, Liu Y et al. 1998. Modification of yeast Cdc53p by the ubiquitin-related protein Rub1p affects function of the SCFCdc4 complex. Genes Dev 12:914–26
    [Google Scholar]
  123. 123. 
    Osaka F, Kawasaki H, Aida N, Saeki M, Chiba T et al. 1998. A new NEDD8-ligating system for cullin-4A. Genes Dev 12:2263–68
    [Google Scholar]
  124. 124. 
    Pan ZQ, Kentsis A, Dias DC, Yamoah K, Wu K. 2004. Nedd8 on cullin: building an expressway to protein destruction. Oncogene 23:1985–97
    [Google Scholar]
  125. 125. 
    Huang DT, Ayrault O, Hunt HW, Taherbhoy AM, Duda DM et al. 2009. E2-RING expansion of the NEDD8 cascade confers specificity to cullin modification. Mol. Cell 33:483–95
    [Google Scholar]
  126. 126. 
    Huang DT, Hunt HW, Zhuang M, Ohi MD, Holton JM, Schulman BA. 2007. Basis for a ubiquitin-like protein thioester switch toggling E1-E2 affinity. Nature 445:394–98
    [Google Scholar]
  127. 127. 
    Chen ZJ, Parent L, Maniatis T. 1996. Site-specific phosphorylation of IκBα by a novel ubiquitination-dependent protein kinase activity. Cell 84:853–62
    [Google Scholar]
  128. 128. 
    Sievers QL, Gasser JA, Cowley GS, Fischer ES, Ebert BL. 2018. Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity. Blood 132:1293–303
    [Google Scholar]
  129. 129. 
    Kawakami T, Chiba T, Suzuki T, Iwai K, Yamanaka K et al. 2001. NEDD8 recruits E2-ubiquitin to SCF E3 ligase. EMBO J 20:4003–12
    [Google Scholar]
  130. 130. 
    Sakata E, Yamaguchi Y, Miyauchi Y, Iwai K, Chiba T et al. 2007. Direct interactions between NEDD8 and ubiquitin E2 conjugating enzymes upregulate cullin-based E3 ligase activity. Nat. Struct. Mol. Biol. 14:167–68
    [Google Scholar]
  131. 131. 
    Kelsall IR, Duda DM, Olszewski JL, Hofmann K, Knebel A et al. 2013. TRIAD1 and HHARI bind to and are activated by distinct neddylated Cullin-RING ligase complexes. EMBO J 32:2848–60
    [Google Scholar]
  132. 132. 
    Horn-Ghetko D, Krist DT, Prabu JR, Baek K, Mulder MPC et al. 2021. Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly. Nature 590:671–76
    [Google Scholar]
  133. 133. 
    Huttenhain R, Xu J, Burton LA, Gordon DE, Hultquist JF et al. 2019. ARIH2 is a Vif-dependent regulator of CUL5-mediated APOBEC3G degradation in HIV infection. Cell Host Microbe 26:86–99.e7
    [Google Scholar]
  134. 134. 
    Dove KK, Kemp HA, Di Bona KR, Reiter KH, Milburn LJ et al. 2017. Two functionally distinct E2/E3 pairs coordinate sequential ubiquitination of a common substrate in Caenorhabditis elegans development. PNAS 114:E6576–84
    [Google Scholar]
  135. 135. 
    Gazdoiu S, Yamoah K, Wu K, Pan ZQ. 2007. Human Cdc34 employs distinct sites to coordinate attachment of ubiquitin to a substrate and assembly of polyubiquitin chains. Mol. Cell. Biol. 27:7041–52
    [Google Scholar]
  136. 136. 
    Ziemba A, Hill S, Sandoval D, Webb K, Bennett EJ, Kleiger G. 2013. Multimodal mechanism of action for the Cdc34 acidic loop: a case study for why ubiquitin-conjugating enzymes have loops and tails. J. Biol. Chem. 288:34882–96
    [Google Scholar]
  137. 137. 
    Ptak C, Prendergast JA, Hodgins R, Kay CM, Chau V, Ellison MJ. 1994. Functional and physical characterization of the cell cycle ubiquitin-conjugating enzyme CDC34 (UBC3). Identification of a functional determinant within the tail that facilitates CDC34 self-association. J. Biol. Chem. 269:26539–45
    [Google Scholar]
  138. 138. 
    Williams KM, Qie S, Atkison JH, Salazar-Arango S, Diehl JA, Olsen SK. 2019. Structural insights into E1 recognition and the ubiquitin-conjugating activity of the E2 enzyme Cdc34. Nat. Commun. 10:3296
    [Google Scholar]
  139. 139. 
    Kleiger G, Saha A, Lewis S, Kuhlman B, Deshaies RJ. 2009. Rapid E2-E3 assembly and disassembly enable processive ubiquitylation of cullin-RING ubiquitin ligase substrates. Cell 139:957–68
    [Google Scholar]
  140. 140. 
    Liwocha J, Krist DT, van der Heden van Noort GJ, Hansen FM, Truong VH et al. 2021. Linkage-specific ubiquitin chain formation depends on a lysine hydrocarbon ruler. Nat. Chem. Biol. 17:272–79
    [Google Scholar]
  141. 141. 
    Lu G, Weng S, Matyskiela M, Zheng X, Fang W et al. 2018. UBE2G1 governs the destruction of cereblon neomorphic substrates. eLife 7:e40958
    [Google Scholar]
  142. 142. 
    Huang H, Ceccarelli DF, Orlicky S, St-Cyr DJ, Ziemba A et al. 2014. E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin. Nat. Chem. Biol. 10:156–63
    [Google Scholar]
  143. 143. 
    Chamovitz DA, Wei N, Osterlund MT, von Arnim AG, Staub JM et al. 1996. The COP9 complex, a novel multisubunit nuclear regulator involved in light control of a plant developmental switch. Cell 86:115–21
    [Google Scholar]
  144. 144. 
    Lyapina S, Cope G, Shevchenko A, Serino G, Tsuge T et al. 2001. Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome. Science 292:1382–85
    [Google Scholar]
  145. 145. 
    Echalier A, Pan Y, Birol M, Tavernier N, Pintard L et al. 2013. Insights into the regulation of the human COP9 signalosome catalytic subunit, CSN5/Jab1. PNAS 110:1273–78
    [Google Scholar]
  146. 146. 
    Lingaraju GM, Bunker RD, Cavadini S, Hess D, Hassiepen U et al. 2014. Crystal structure of the human COP9 signalosome. Nature 512:161–65
    [Google Scholar]
  147. 147. 
    Faull SV, Lau AMC, Martens C, Ahdash Z, Hansen K et al. 2019. Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome. Nat. Commun. 10:3814
    [Google Scholar]
  148. 148. 
    Schwechheimer C, Serino G, Callis J, Crosby WL, Lyapina S et al. 2001. Interactions of the COP9 signalosome with the E3 ubiquitin ligase SCFTIR1 in mediating auxin response. Science 292:1379–82
    [Google Scholar]
  149. 149. 
    Cope GA, Suh GS, Aravind L, Schwarz SE, Zipursky SL et al. 2002. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science 298:608–11
    [Google Scholar]
  150. 150. 
    Feng S, Shen Y, Sullivan JA, Rubio V, Xiong Y et al. 2004. Arabidopsis CAND1, an unmodified CUL1-interacting protein, is involved in multiple developmental pathways controlled by ubiquitin/proteasome-mediated protein degradation. Plant Cell 16:1870–82
    [Google Scholar]
  151. 151. 
    Schmidt MW, McQuary PR, Wee S, Hofmann K, Wolf DA. 2009. F-box-directed CRL complex assembly and regulation by the CSN and CAND1. Mol. Cell 35:586–97
    [Google Scholar]
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