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Lysine-targeting specificity in ubiquitin and ubiquitin-like modification pathways

Nature Structural & Molecular Biology volume 21, pages 308–316 (2014)Cite this article

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Abstract

Ubiquitin and ubiquitin-like modifications are central to virtually all cellular signaling pathways. They occur primarily on lysine residues of target proteins and stimulate a large number of downstream signals. The diversity of these signals depends on the type, location and dynamics of the modification, but the role of the exact site of modification and the selectivity for specific lysines are poorly understood. Here we review the current literature on lysine specificity in these modifications, and we highlight the known signaling mechanisms and the open questions that pose future challenges to ubiquitin research.

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Figure 1: Modes of target recognition.
Figure 2: E3-mediated lysine specificity.
Figure 3: Specificity for amino groups in ubiquitin-chain formation.
Figure 4: Modes of recognition by readers.

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References

  1. Hochstrasser, M. Origin and function of ubiquitin-like proteins. Nature 458, 422–429 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hoege, C., Pfander, B., Moldovan, G.L., Pyrowolakis, G. & Jentsch, S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419, 135–141 (2002).In this paper, the links between E2–E3, Rad6–Rad18 and a specific lysine on a target (K164 on PCNA) are identified.

    Article  CAS  PubMed  Google Scholar 

  3. Mattiroli, F. et al. RNF168 ubiquitinates K13–15 on H2A/H2AX to drive DNA damage signaling. Cell 150, 1182–1195 (2012).This work establishes a structural and functional separation between two different lysines on a single target by E3 ligases in Polycomb and DNA-damage signaling.

    Article  CAS  PubMed  Google Scholar 

  4. Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Sun, Z.W. & Allis, C.D. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature 418, 104–108 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Dorsman, J.C. et al. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell. Oncol. 29, 211–218 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sims, A.E. et al. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat. Struct. Mol. Biol. 14, 564–567 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Smogorzewska, A. et al. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129, 289–301 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hunt, L.T. & Dayhoff, M.O. Amino-terminal sequence identity of ubiquitin and the nonhistone component of nuclear protein A24. Biochem. Biophys. Res. Commun. 74, 650–655 (1977).

    Article  CAS  PubMed  Google Scholar 

  10. Tatham, M.H., Matic, I., Mann, M. & Hay, R.T. Comparative proteomic analysis identifies a role for SUMO in protein quality control. Sci. Signal. 4, rs4 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Wagner, S.A. et al. A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol. Cell. Proteomics 10, M111 013284 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Kessler, B.M. Ubiquitin -omics reveals novel networks and associations with human disease. Curr. Opin. Chem. Biol. 17, 59–65 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Danielsen, J.M. et al. Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level. Mol. Cell. Proteomics 10, M110 003590 (2011).

    Article  PubMed  CAS  Google Scholar 

  14. Behrends, C. & Harper, J.W. Constructing and decoding unconventional ubiquitin chains. Nat. Struct. Mol. Biol. 18, 520–528 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Xu, G., Paige, J.S. & Jaffrey, S.R. Global analysis of lysine ubiquitination by ubiquitin remnant immunoaffinity profiling. Nat. Biotechnol. 28, 868–873 (2010).In this work, the use of anti-diglycine antibody enables efficient proteomic analysis of ubiquitin target sites.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sarraf, S.A. et al. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496, 372–376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Deshaies, R.J. & Joazeiro, C.A. RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78, 399–434 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Kamadurai, H.B. et al. Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3. eLife 2, e00828 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Varshavsky, A. Naming a targeting signal. Cell 64, 13–15 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Winston, J.T. et al. The SCFβ-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro. Genes Dev. 13, 270–283 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Orlicky, S., Tang, X., Willems, A., Tyers, M. & Sicheri, F. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell 112, 243–256 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Jin, J. et al. SCFβ-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev. 17, 3062–3074 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bentley, M.L. et al. Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex. EMBO J. 30, 3285–3297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Buchwald, G. et al. Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins Bmi1 and Ring1b. EMBO J. 25, 2465–2474 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Petroski, M.D. & Deshaies, R.J. Function and regulation of cullin–RING ubiquitin ligases. Nat. Rev. Mol. Cell Biol. 6, 9–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Zheng, N. et al. Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex. Nature 416, 703–709 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Smit, J.J. & Sixma, T.K. RBR E3-ligases at work. EMBO Rep. 15, 142–154 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Duda, D.M. et al. Structural regulation of cullin-RING ubiquitin ligase complexes. Curr. Opin. Struct. Biol. 21, 257–264 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fischer, E.S. et al. The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation. Cell 147, 1024–1039 (2011).Here the concept of a nonspecific ubiquitination zone reaching beyond a specific target is suggested for CUL4 complexes.

    Article  CAS  PubMed  Google Scholar 

  30. Petroski, M.D. & Deshaies, R.J. Context of multiubiquitin chain attachment influences the rate of Sic1 degradation. Mol. Cell 11, 1435–1444 (2003).This work shows that a single polyubiquitin chain is sufficient for Sic1 degradation and that chain position has an important role in protein degradation rates.

    Article  CAS  PubMed  Google Scholar 

  31. Tang, X. et al. Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination. Cell 129, 1165–1176 (2007).This paper shows how a zone of lysines can be reached by a single E3 ligase.

    Article  CAS  PubMed  Google Scholar 

  32. King, R.W., Deshaies, R.J., Peters, J.M. & Kirschner, M.W. How proteolysis drives the cell cycle. Science 274, 1652–1659 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Skaar, J.R. & Pagano, M. Control of cell growth by the SCF and APC/C ubiquitin ligases. Curr. Opin. Cell Biol. 21, 816–824 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Min, M., Mayor, U. & Lindon, C. Ubiquitination site preferences in anaphase promoting complex/cyclosome (APC/C) substrates. Open Bio. 3, 130097 (2013).

    Article  CAS  Google Scholar 

  35. Skowyra, D., Craig, K.L., Tyers, M., Elledge, S.J. & Harper, J.W. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91, 209–219 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Sadowski, M., Suryadinata, R., Lai, X., Heierhorst, J. & Sarcevic, B. Molecular basis for lysine specificity in the yeast ubiquitin-conjugating enzyme Cdc34. Mol. Cell. Biol. 30, 2316–2329 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Latres, E., Chiaur, D.S. & Pagano, M. The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin. Oncogene 18, 849–854 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Wu, G. et al. Structure of a β-TrCP1-Skp1-β-catenin complex: destruction motif binding and lysine specificity of the SCFβ-TrCP1 ubiquitin ligase. Mol. Cell 11, 1445–1456 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Baldi, L., Brown, K., Franzoso, G. & Siebenlist, U. Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of IκBα. J. Biol. Chem. 271, 376–379 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Vuillard, L., Nicholson, J. & Hay, R.T. A complex containing (TrCP recruits Cdc34 to catalyse ubiquitination of IκBα. FEBS Lett. 455, 311–314 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Kaiser, P., Flick, K., Wittenberg, C. & Reed, S.I. Regulation of transcription by ubiquitination without proteolysis: Cdc34/SCF(Met30)-mediated inactivation of the transcription factor Met4. Cell 102, 303–314 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Menant, A., Baudouin-Cornu, P., Peyraud, C., Tyers, M. & Thomas, D. Determinants of the ubiquitin-mediated degradation of the Met4 transcription factor. J. Biol. Chem. 281, 11744–11754 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Flick, K., Raasi, S., Zhang, H., Yen, J.L. & Kaiser, P. A ubiquitin-interacting motif protects polyubiquitinated Met4 from degradation by the 26S proteasome. Nat. Cell Biol. 8, 509–515 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Chen, J. & Chen, Z.J. Regulation of NF-κB by ubiquitination. Curr. Opin. Immunol. 25, 4–12 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dou, H., Buetow, L., Sibbet, G.J., Cameron, K. & Huang, D.T. Essentiality of a non-RING element in priming donor ubiquitin for catalysis by a monomeric E3. Nat. Struct. Mol. Biol. 20, 982–986 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Lee, J.T. & Gu, W. The multiple levels of regulation by p53 ubiquitination. Cell Death Differ. 17, 86–92 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Rodriguez, M.S., Desterro, J.M., Lain, S., Lane, D.P. & Hay, R.T. Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol. Cell. Biol. 20, 8458–8467 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shiloh, Y., Shema, E., Moyal, L. & Oren, M. RNF20–RNF40: a ubiquitin-driven link between gene expression and the DNA damage response. FEBS Lett. 585, 2795–2802 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Dupont, S. et al. FAM/USP9x, a deubiquitinating enzyme essential for TGFβ signaling, controls Smad4 monoubiquitination. Cell 136, 123–135 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Garner, E. & Smogorzewska, A. Ubiquitylation and the Fanconi anemia pathway. FEBS Lett. 585, 2853–2860 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Cole, A.R., Lewis, L.P. & Walden, H. The structure of the catalytic subunit FANCL of the Fanconi anemia core complex. Nat. Struct. Mol. Biol. 17, 294–298 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Alpi, A.F., Pace, P.E., Babu, M.M. & Patel, K.J. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol. Cell 32, 767–777 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Moldovan, G.L., Pfander, B. & Jentsch, S. PCNA, the maestro of the replication fork. Cell 129, 665–679 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Parker, J.L. & Ulrich, H.D. Mechanistic analysis of PCNA poly-ubiquitylation by the ubiquitin protein ligases Rad18 and Rad5. EMBO J. 28, 3657–3666 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Langerak, P., Nygren, A.O., Krijger, P.H., van den Berk, P.C. & Jacobs, H. A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification. J. Exp. Med. 204, 1989–1998 (2007).This work shows that a single lysine on PCNA is crucial for translesion synthesis in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hibbert, R.G., Huang, A., Boelens, R. & Sixma, T.K. E3 ligase Rad18 promotes monoubiquitination rather than ubiquitin chain formation by E2 enzyme Rad6. Proc. Natl. Acad. Sci. USA 108, 5590–5595 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hibbert, R.G. & Sixma, T.K. Intrinsic flexibility of ubiquitin on proliferating cell nuclear antigen (PCNA) in translesion synthesis. J. Biol. Chem. 287, 39216–39223 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cao, R., Tsukada, Y. & Zhang, Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol. Cell 20, 845–854 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. de Napoles, M. et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell 7, 663–676 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Gatti, M. et al. A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by RNF168 ubiquitin ligase. Cell Cycle 11, 2538–2544 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fradet-Turcotte, A. et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499, 50–54 (2013).This work shows how site-specific ubiquitin modification at K15 on H2A stimulates a specific downstream signal by recruiting reader protein 53BP1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mattiroli, F., Uckelmann, M., Sahtoe, D.D., Van Dijk, W.J. & Sixma, T.K. The nucleosome acidic patch plays a critical role in RNF168-dependent ubiquitination of histone H2A. Nat. Commun. 5, 3291 (2014).Here a role for distal regions of the target in promoting site-directed catalysis is identified.

    Article  PubMed  CAS  Google Scholar 

  64. Marchese, A. & Trejo, J. Ubiquitin-dependent regulation of G protein-coupled receptor trafficking and signaling. Cell. Signal. 25, 707–716 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Stawiecka-Mirota, M. et al. Targeting of Sna3p to the endosomal pathway depends on its interaction with Rsp5p and multivesicular body sorting on its ubiquitylation. Traffic 8, 1280–1296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Duda, D.M. et al. Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoinhibition of an Ariadne-family E3 and insights into ligation mechanism. Structure 21, 1030–1041 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Spratt, D.E., Mercier, P. & Shaw, G.S. Structure of the HHARI catalytic domain shows glimpses of a HECT E3 ligase. PLoS ONE 8, e74047 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wauer, T. & Komander, D. Structure of the human Parkin ligase domain in an autoinhibited state. EMBO J. 32, 2099–2112 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Trempe, J.F. et al. Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science 340, 1451–1455 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Stieglitz, B. et al. Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature 503, 422–426 (2013).This work shows how the acceptor ubiquitin is presented for N-terminal ubiquitin-chain formation by the RING2-LDD region of HOIP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kelsall, I.R. et al. TRIAD1 and HHARI bind to and are activated by distinct neddylated Cullin-RING ligase complexes. EMBO J. 32, 2848–2860 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Smit, J.J. et al. Target specificity of the E3 ligase LUBAC for ubiquitin and NEMO relies on different minimal requirements. J. Biol. Chem. 288, 31728–31737 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wenzel, D.M. & Klevit, R.E. Following Ariadne's thread: a new perspective on RBR ubiquitin ligases. BMC Biol. 10, 24 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chen, Z. & Pickart, C.M. A 25-kilodalton ubiquitin carrier protein (E2) catalyzes multi-ubiquitin chain synthesis via lysine 48 of ubiquitin. J. Biol. Chem. 265, 21835–21842 (1990).

    Article  CAS  PubMed  Google Scholar 

  75. Hofmann, R.M. & Pickart, C.M. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96, 645–653 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Eddins, M.J., Carlile, C.M., Gomez, K.M., Pickart, C.M. & Wolberger, C. Mms2–Ubc13 covalently bound to ubiquitin reveals the structural basis of linkage-specific polyubiquitin chain formation. Nat. Struct. Mol. Biol. 13, 915–920 (2006).This structure reveals how the ubiquitin E2 variant Mms2 promotes K63-linked ubiquitin-chain formation by positioning the acceptor ubiquitin.

    Article  CAS  PubMed  Google Scholar 

  77. Williamson, A. et al. Identification of a physiological E2 module for the human anaphase-promoting complex. Proc. Natl. Acad. Sci. USA 106, 18213–18218 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wickliffe, K.E., Lorenz, S., Wemmer, D.E., Kuriyan, J. & Rape, M. The mechanism of linkage-specific ubiquitin chain elongation by a single-subunit E2. Cell 144, 769–781 (2011).This work details how the E2 enzyme Ube2s provides the specificity for K11-linked ubiquitin-chain formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Plechanovová, A., Jaffray, E.G., Tatham, M.H., Naismith, J.H. & Hay, R.T. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489, 115–120 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Pruneda, J.N. et al. Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Mol. Cell 47, 933–942 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Dou, H., Buetow, L., Sibbet, G.J., Cameron, K. & Huang, D.T. BIRC7–E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nat. Struct. Mol. Biol. 19, 876–883 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Scaglione, K.M. et al. The ubiquitin-conjugating enzyme (E2) Ube2w ubiquitinates the N terminus of substrates. J. Biol. Chem. 288, 18784–18788 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tatham, M.H., Plechanovova, A., Jaffray, E.G., Salmen, H. & Hay, R.T. Ube2W conjugates ubiquitin to α-amino groups of protein N-termini. Biochem. J. 453, 137–145 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Kim, H.C. & Huibregtse, J.M. Polyubiquitination by HECT E3s and the determinants of chain type specificity. Mol. Cell. Biol. 29, 3307–3318 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Maspero, E. et al. Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming. Nat. Struct. Mol. Biol. 20, 696–701 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Stieglitz, B., Morris-Davies, A.C., Koliopoulos, M.G., Christodoulou, E. & Rittinger, K. LUBAC synthesizes linear ubiquitin chains via a thioester intermediate. EMBO Rep. 13, 840–846 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Smit, J.J. et al. The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension. EMBO J. 31, 3833–3844 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bernier-Villamor, V., Sampson, D.A., Matunis, M.J. & Lima, C.D. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell 108, 345–356 (2002).This first structure of an E2–UBL-target complex defines the structural details that regulate SUMOylation at consensus sites.

    Article  CAS  PubMed  Google Scholar 

  89. Sampson, D.A., Wang, M. & Matunis, M.J. The small ubiquitin-like modifier-1 (SUMO-1) consensus sequence mediates Ubc9 binding and is essential for SUMO-1 modification. J. Biol. Chem. 276, 21664–21669 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Desterro, J.M., Rodriguez, M.S. & Hay, R.T. SUMO-1 modification of IκBκ inhibits NF-κB activation. Mol. Cell 2, 233–239 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Mohideen, F. et al. A molecular basis for phosphorylation-dependent SUMO conjugation by the E2 UBC9. Nat. Struct. Mol. Biol. 16, 945–952 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hietakangas, V. et al. PDSM, a motif for phosphorylation-dependent SUMO modification. Proc. Natl. Acad. Sci. USA 103, 45–50 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Yang, X.J. & Gregoire, S. A recurrent phospho-sumoyl switch in transcriptional repression and beyond. Mol. Cell 23, 779–786 (2006).

    Article  PubMed  CAS  Google Scholar 

  94. Mahajan, R., Gerace, L. & Melchior, F. Molecular characterization of the SUMO-1 modification of RanGAP1 and its role in nuclear envelope association. J. Cell Biol. 140, 259–270 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Pichler, A., Knipscheer, P., Saitoh, H., Sixma, T.K. & Melchior, F. The RanBP2 SUMO E3 ligase is neither HECT- nor RING-type. Nat. Struct. Mol. Biol. 11, 984–991 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Reverter, D. & Lima, C.D. Insights into E3 ligase activity revealed by a SUMO–RanGAP1–Ubc9–Nup358 complex. Nature 435, 687–692 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Werner, A., Flotho, A. & Melchior, F. The RanBP2/RanGAP1*SUMO1/Ubc9 complex is a multisubunit SUMO E3 ligase. Mol. Cell 46, 287–298 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Pfander, B., Moldovan, G.L., Sacher, M., Hoege, C. & Jentsch, S. SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase. Nature 436, 428–433 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Yunus, A.A. & Lima, C.D. Structure of the Siz/PIAS SUMO E3 ligase Siz1 and determinants required for SUMO modification of PCNA. Mol. Cell 35, 669–682 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Pichler, A. et al. SUMO modification of the ubiquitin-conjugating enzyme E2–25K. Nat. Struct. Mol. Biol. 12, 264–269 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Psakhye, I. & Jentsch, S. Protein group modification and synergy in the SUMO pathway as exemplified in DNA repair. Cell 151, 807–820 (2012).This work presents the concept of a wave of SUMO-SIM interactions providing a cellular signal after DNA damage.

    Article  CAS  PubMed  Google Scholar 

  102. Reindle, A. et al. Multiple domains in Siz SUMO ligases contribute to substrate selectivity. J. Cell Sci. 119, 4749–4757 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Scott, D.C. et al. A dual E3 mechanism for Rub1 ligation to Cdc53. Mol. Cell 39, 784–796 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kurz, T. et al. Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation. Mol. Cell 29, 23–35 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Sims, J.J. & Cohen, R.E. Linkage-specific avidity defines the lysine 63-linked polyubiquitin-binding preference of rap80. Mol. Cell 33, 775–783 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Komander, D. & Rape, M. The ubiquitin code. Annu. Rev. Biochem. 81, 203–229 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Dikic, I., Wakatsuki, S. & Walters, K.J. Ubiquitin-binding domains: from structures to functions. Nat. Rev. Mol. Cell Biol. 10, 659–671 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Polo, S. et al. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416, 451–455 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Bienko, M. et al. Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310, 1821–1824 (2005).This work proposes, for the first time, the concept of specific readers that combine ubiquitin or UBL binding with specific target interactions.

    Article  CAS  PubMed  Google Scholar 

  110. MacKay, C. et al. Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell 142, 65–76 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kratz, K. et al. Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell 142, 77–88 (2010).

    Article  CAS  PubMed  Google Scholar 

  112. Smogorzewska, A. et al. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol. Cell 39, 36–47 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Liu, T., Ghosal, G., Yuan, J., Chen, J. & Huang, J. FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science 329, 693–696 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Huang, M. & D'Andrea, A.D. A new nuclease member of the FAN club. Nat. Struct. Mol. Biol. 17, 926–928 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Richly, H. et al. Transcriptional activation of polycomb-repressed genes by ZRF1. Nature 468, 1124–1128 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Yuan, J., Ghosal, G. & Chen, J. The HARP-like domain-containing protein AH2/ZRANB3 binds to PCNA and participates in cellular response to replication stress. Mol. Cell 47, 410–421 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Weston, R., Peeters, H. & Ahel, D. ZRANB3 is a structure-specific ATP-dependent endonuclease involved in replication stress response. Genes Dev. 26, 1558–1572 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ciccia, A. et al. Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress. Mol. Cell 47, 396–409 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Hecker, C.M., Rabiller, M., Haglund, K., Bayer, P. & Dikic, I. Specification of SUMO1- and SUMO2-interacting motifs. J. Biol. Chem. 281, 16117–16127 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Papouli, E. et al. Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. Mol. Cell 19, 123–133 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Armstrong, A.A., Mohideen, F. & Lima, C.D. Recognition of SUMO-modified PCNA requires tandem receptor motifs in Srs2. Nature 483, 59–63 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Moldovan, G.L. et al. Inhibition of homologous recombination by the PCNA-interacting protein PARI. Mol. Cell 45, 75–86 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Pilla, E. et al. A novel SUMO1-specific interacting motif in dipeptidyl peptidase 9 (DPP9) that is important for enzymatic regulation. J. Biol. Chem. 287, 44320–44329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Keusekotten, K. et al. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell 153, 1312–1326 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Nijman, S.M. et al. A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773–786 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Cooper, E.M. et al. K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO J. 28, 621–631 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Mevissen, T.E. et al. OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell 154, 169–184 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bremm, A., Freund, S.M. & Komander, D. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nat. Struct. Mol. Biol. 17, 939–947 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Faesen, A.C. et al. The differential modulation of USP activity by internal regulatory domains, interactors and eight ubiquitin chain types. Chem. Biol. 18, 1550–1561 (2011).

    Article  CAS  PubMed  Google Scholar 

  130. Schulz, S. et al. Ubiquitin-specific protease-like 1 (USPL1) is a SUMO isopeptidase with essential, non-catalytic functions. EMBO Rep. 13, 930–938 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hickey, C.M., Wilson, N.R. & Hochstrasser, M. Function and regulation of SUMO proteases. Nat. Rev. Mol. Cell Biol. 13, 755–766 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wei, N., Serino, G. & Deng, X.W. The COP9 signalosome: more than a protease. Trends Biochem. Sci. 33, 592–600 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Klevit for discussion and M. Uckelmann, D. Sahtoe and A. Murachelli for critical reading of the manuscript. Funding is from European Research Council advanced grant 249997 and Netherlands Organisation for Scientific Research-Chemical Sciences (NWO-CW) TOP grant 714.012.001 and Cancer Genomics Centre (CGC.nl).

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  1. Francesca Mattiroli

    Present address: Present address: Howard Hughes Medical Institute, Department of Molecular and Radiological Biosciences, Colorado State University, Fort Collins, Colorado, USA.,

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  1. Division of Biochemistry, Cancer Genomics Center, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Francesca Mattiroli & Titia K Sixma

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Mattiroli, F., Sixma, T. Lysine-targeting specificity in ubiquitin and ubiquitin-like modification pathways. Nat Struct Mol Biol 21, 308–316 (2014). https://doi.org/10.1038/nsmb.2792

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