Structural basis of Keap1 interactions with Nrf2

Free Radical Biology and Medicine

Volumn 88, Issue Part B, 2015, Pages 101-107

  Canning, Peter ^a,b   Sorrell, Fiona J ^a   Bullock, Alex N ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

BTB; Cullin; Free radicals; Keap1; Kelch; Nrf2; Ubiquitin

Indexed keywords

KELCH LIKE ECH ASSOCIATED PROTEIN 1; TRANSCRIPTION FACTOR NRF2; SIGNAL PEPTIDE;

ARTICLE; DIMERIZATION; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN ASSEMBLY; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; ANIMAL; CHEMISTRY; METABOLISM; MOLECULAR MODEL; OXIDATIVE STRESS; PHYSIOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MODELS, MOLECULAR; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS; SIGNAL TRANSDUCTION;

EID: 84970038593     PISSN: 08915849     EISSN: 18734596     Source Type: Journal    
DOI: 10.1016/j.freeradbiomed.2015.05.034     Document Type: Review

References (73)

1. P. Moi, K. Chan, I. Asunis, A. Cao, and Y.W. Kan Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region Proc. Natl. Acad. Sci. USA 91 1994 9926 9930
2. G.P. Sykiotis, and D. Bohmann Stress-activated cap'n'collar transcription factors in aging and human disease Sci. Signaling 3 2010
3. J.D. Hayes, and A.T. Dinkova-Kostova The Nrf2 regulatory network provides an interface between redox and intermediary metabolism Trends Biochem. Sci. 39 2014 199 218
4. T. Suzuki, H. Motohashi, and M. Yamamoto Toward clinical application of the Keap1-Nrf2 pathway Trends Pharmacol. Sci. 34 2013 340 346
5. A. Giudice, and M. Montella Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention Bioessays 28 2006 169 181
6. H. Motohashi, F. Katsuoka, J.D. Engel, and M. Yamamoto Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway Proc. Natl. Acad. Sci. USA 101 2004 6379 6384
7. K. Itoh, T. Chiba, S. Takahashi, T. Ishii, K. Igarashi, and et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements Biochem. Biophys. Res. Commun 236 1997 313 322
8. T.H. Rushmore, and C.B. Pickett Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene: characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants J. Biol. Chem. 265 1990 14648 14653
9. K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, K. Igarashi, and et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain Genes Dev. 13 1999 76 86
10. K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, T. O'Connor, and et al. Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles Genes Cells 8 2003 379 391
11. M. Furukawa, and Y. Xiong BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase Mol. Cell. Biol. 25 2005 162 171
12. M. McMahon, K. Itoh, M. Yamamoto, and J.D. Hayes Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression J. Biol. Chem. 278 2003 21592 21600
13. A. Kobayashi, M.I. Kang, H. Okawa, M. Ohtsuji, Y. Zenke, and et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2 Mol. Cell. Biol. 24 2004 7130 7139
14. S.B. Cullinan, J.D. Gordan, J. Jin, J.W. Harper, and J.A. Diehl The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase Mol. Cell. Biol. 24 2004 8477 8486
15. D.D. Zhang, S.C. Lo, J.V. Cross, D.J. Templeton, and M. Hannink Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex Mol. Cell. Biol. 24 2004 10941 10953
16. W. Hur, and N.S. Gray Small molecule modulators of antioxidant response pathway Curr. Opin. Chem. Biol. 15 2011 162 173
17. K.R. Sekhar, G. Rachakonda, and M.L. Freeman Cysteine-based regulation of the CUL3 adaptor protein Keap1 Toxicol. Appl. Pharmacol 244 2010 21 26
18. A.T. Dinkova-Kostova, W.D. Holtzclaw, R.N. Cole, K. Itoh, N. Wakabayashi, and et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants Proc. Natl. Acad. Sci. USA 99 2002 11908 11913
19. D.D. Zhang, and M. Hannink Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress Mol. Cell. Biol 23 2003 8137 8151
20. A.L. Levonen, A. Landar, A. Ramachandran, E.K. Ceaser, D.A. Dickinson, and et al. Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products Biochem. J. 378 2004 373 382
21. N. Wakabayashi, A.T. Dinkova-Kostova, W.D. Holtzclaw, M.I. Kang, A. Kobayashi, and et al. Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers Proc. Natl. Acad. Sci. USA 101 2004 2040 2045
22. B. Gao, A. Doan, and B.M. Hybertson The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders Clin. Pharmacol 6 2014 19 34
23. P. Canning, and A.N. Bullock New strategies to inhibit Keap1 and the Cul3-based E3 ubiquitin ligases Biochem. Soc. Trans. 42 2014 103 107
24. K.I. Tong, Y. Katoh, H. Kusunoki, K. Itoh, T. Tanaka, and et al. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model Mol. Cell. Biol. 26 2006 2887 2900
25. M. McMahon, N. Thomas, K. Itoh, M. Yamamoto, and J.D. Hayes Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron J. Biol. Chem 279 2004 31556 31567
26. P. Rada, A.I. Rojo, S. Chowdhry, M. McMahon, J.D. Hayes, and et al. SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner Mol. Cell. Biol. 31 2011 1121 1133
27. S. Chowdhry, Y. Zhang, M. McMahon, C. Sutherland, A. Cuadrado, and et al. Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity Oncogene 32 2013 3765 3781
28. P. Rada, A.I. Rojo, N. Evrard-Todeschi, N.G. Innamorato, A. Cotte, and et al. Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/beta-TrCP axis Mol. Cell. Biol 32 2012 3486 3499
29. P. Nioi, T. Nguyen, P.J. Sherratt, and C.B. Pickett The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation Mol. Cell. Biol. 25 2005 10895 10906
30. Y. Katoh, K. Itoh, E. Yoshida, M. Miyagishi, A. Fukamizu, and et al. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription Genes Cells 6 2001 857 868
31. H. Wang, K. Liu, M. Geng, P. Gao, X. Wu, and et al. RXRalpha inhibits the Nrf2-ARE signaling pathway through a direct interaction with the Neh7 domain of Nrf2 Cancer Res. 73 2013 3097 3108
32. P. Canning, C.D. Cooper, T. Krojer, J.W. Murray, A.C. Pike, and et al. Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases J. Biol. Chem. 288 2013 7803 7814
33. B.S. Dhanoa, T. Cogliati, A.G. Satish, E.A. Bruford, and J.S. Friedman Update on the Kelch-like (KLHL) gene family Hum. Genomics 7 2013 13
34. O. Albagli, P. Dhordain, C. Deweindt, G. Lecocq, and D. Leprince The BTB/POZ domain: a new protein-protein interaction motif common to DNA- and actin-binding proteins Cell Growth Differ. 6 1995 1193 1198
35. A. Cleasby, J. Yon, P.J. Day, C. Richardson, I.J. Tickle, and et al. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO PLoS One 9 2014 e98896
36. S.C. Lo, X. Li, M.T. Henzl, L.J. Beamer, and M. Hannink Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling EMBO J. 25 2006 3605 3617
37. B. Padmanabhan, K.I. Tong, T. Ohta, Y. Nakamura, M. Scharlock, and et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer Mol. Cell 21 2006 689 700
38. K.I. Tong, B. Padmanabhan, A. Kobayashi, C. Shang, Y. Hirotsu, and et al. Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response Mol. Cell. Biol. 27 2007 7511 7521
39. T. Fukutomi, K. Takagi, T. Mizushima, N. Ohuchi, and M. Yamamoto Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1 Mol. Cell. Biol. 34 2014 832 846
40. A.L. Eggler, G. Liu, J.M. Pezzuto, R.B. van Breemen, and A.D. Mesecar Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2 Proc. Natl. Acad. Sci. USA 102 2005 10070 10075
41. L.J. Beamer, X. Li, C.A. Bottoms, and M. Hannink Conserved solvent and side-chain interactions in the 1.35 Angstrom structure of the Kelch domain of Keap1 Acta Crystallogr. D Biol. Crystallogr 61 2005 1335 1342
42. X. Li, D. Zhang, M. Hannink, and L.J. Beamer Crystal structure of the Kelch domain of human Keap1 J. Biol. Chem. 279 2004 54750 54758
43. J. Adams, R. Kelso, and L. Cooley The kelch repeat superfamily of proteins: propellers of cell function Trends Cell Biol. 10 2000 17 24
44. T. Ogura, K.I. Tong, K. Mio, Y. Maruyama, H. Kurokawa, and et al. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains Proc. Natl. Acad. Sci. USA 107 2010 2842 2847
45. K.I. Tong, A. Kobayashi, F. Katsuoka, and M. Yamamoto Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism Biol. Chem. 387 2006 1311 1320
46. A. Singh, V. Misra, R.K. Thimmulappa, H. Lee, S. Ames, and et al. Dysfunctional Keap1-Nrf2 interaction in non-small-cell lung cancer PLoS Med 3 2006 e420
47. T. Shibata, T. Ohta, K.I. Tong, A. Kokubu, R. Odogawa, and et al. Cancer related mutations in Nrf2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy Proc. Natl. Acad. Sci. USA 105 2008 13568 13573
48. A. Singh, M. Bodas, N. Wakabayashi, F. Bunz, and S. Biswal Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance Antioxid. Redox Signaling 13 2010 1627 1637
49. P. Zhang, A. Singh, S. Yegnasubramanian, D. Esopi, P. Kombairaju, and et al. Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth Mol. Cancer Ther. 9 2010 336 346
50. K.F. Kelly, and J.M. Daniel POZ for effect - POZ-ZF transcription factors in cancer and development Trends Cell Biol. 16 2006 578 587
51. R. Perez-Torrado, D. Yamada, and P.A. Defossez Born to bind: the BTB protein-protein interaction domain Bioessays 28 2006 1194 1202
52. P.J. Stogios, G.S. Downs, J.J. Jauhal, S.K. Nandra, and G.G. Prive Sequence and structural analysis of BTB domain proteins Genome Biol. 6 2005 R82
53. K.F. Ahmad, C.K. Engel, and G.G. Prive Crystal structure of the BTB domain from PLZF Proc. Natl. Acad. Sci. USA 95 1998 12123 12128
54. I. Sumara, M. Quadroni, C. Frei, M.H. Olma, G. Sumara, and et al. A Cul3-based E3 ligase removes Aurora B from mitotic chromosomes, regulating mitotic progression and completion of cytokinesis in human cells Dev. Cell 12 2007 887 900
55. L. Pintard, A. Willems, and M. Peter Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family EMBO J. 23 2004 1681 1687
56. A.X. Ji, and G.G. Privé Crystal structure of KLHL3 in complex with Cullin3 PLoS One 8 2013 e60445
57. E. Zimmerman, B. Schulman, and N. Zheng Structural assembly of cullin-RING ubiquitin ligase complexes Curr. Opin. Struct. Biol. 20 2010 714 721
58. M. Zhuang, M.F. Calabrese, J. Liu, M.B. Waddell, A. Nourse, and et al. Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases Mol. Cell 36 2009 39 50
59. N. Zheng, B.A. Schulman, L. Song, J.J. Miller, P.D. Jeffrey, and et al. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex Nature 416 2002 703 709
60. W.J. Errington, M.Q. Khan, S.A. Bueler, J.L. Rubinstein, A. Chakrabartty, and et al. Adaptor protein self-assembly drives the control of a Cullin-RING ubiquitin ligase Structure 20 2012 1141 1153
61. P.J. Stogios, and G.G. Prive The BACK domain in BTB-kelch proteins Trends Biochem. Sci. 29 2004 634 637
62. D.M. Duda, L.A. Borg, D.C. Scott, H.W. Hunt, M. Hammel, and et al. Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation Cell 134 2008 995 1006
63. B.A. Schulman, A.C. Carrano, P.D. Jeffrey, Z. Bowen, E.R. Kinnucan, and et al. Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex Nature 408 2000 381 386
64. A.N. Bullock, J.É. Debreczeni, A.M. Edwards, M. Sundström, and S. Knapp Crystal structure of the SOCS2-elongin C-elongin B complex defines a prototypical SOCS box ubiquitin ligase Proc. Natl. Acad. Sci. USA 103 2006 7637 7642
65. C.E. Stebbins, W.G. Kaelin, and N.P. Pavletich Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function Science 284 1999 455 461
66. H.C. Nguyen, H. Yang, J.L. Fribourgh, L.S. Wolfe, and Y. Xiong Insights into Cullin-RING E3 ubiquitin ligase recruitment: structure of the VHL-EloBC-Cul2 complex Structure 23 2015 441 449
67. Y.K. Kim, M.J. Kwak, B. Ku, H.Y. Suh, K. Joo, and et al. Structural basis of intersubunit recognition in elongin BC-cullin 5-SOCS box ubiquitin-protein ligase complexes Acta Crystallogr. D Biol. Crystallogr 69 2013 1587 1597
68. D. Dubey, B.C. Kieseier, H.P. Hartung, B. Hemmer, C. Warnke, and et al. Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety Expert Rev. Neurother 15 2015 339 346
69. M. McMahon, N. Thomas, K. Itoh, M. Yamamoto, and J.D. Hayes Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex J. Biol. Chem. 281 2006 24756 24768
70. E. Jnoff, C. Albrecht, J.J. Barker, O. Barker, E. Beaumont, and et al. Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex ChemMedChem 9 2014 699 705
71. D. Marcotte, W. Zeng, J.C. Hus, A. McKenzie, C. Hession, and et al. Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism Bioorg. Med. Chem. 21 2013 4011 4019
72. F.R. Schumacher, F.J. Sorrell, D.R. Alessi, A.N. Bullock, and T. Kurz Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation Biochem. J. 460 2014 237 246
73. C.H. Gray, L.C. McGarry, H.J. Spence, A. Riboldi-Tunnicliffe, and B.W. Ozanne Novel beta-propeller of the BTB-Kelch protein Krp1 provides a binding site for Lasp-1 that is necessary for pseudopodial extension J. Biol. Chem. 284 2009 30498 30507