Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism

References

Bell, E.L., Emerling, B.M., and Chandel, N.S. (2005). Mitochondrial regulation of oxygen sensing. Mitochondrion5, 322–332.10.1016/j.mito.2005.06.005Search in Google Scholar

Berra, E., Ginouves, A., and Pouyssegur, J. (2006). The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling. EMBO Rep.7, 41–45.10.1038/sj.embor.7400598Search in Google Scholar

Bokoch, G.M. (1994). Regulation of the human neutrophil NADPH oxidase by the Rac GTP-binding proteins. Cur. Opin. Cell. Biol.6, 212–218.10.1016/0955-0674(94)90138-4Search in Google Scholar

Bonizzi, G., Piette, J., Schoonbroodt, S., Greimers, R., Havard, L., Merville, M.P., and Bours, V. (1999). Reactive oxygen intermediate-dependent NF-κB activation by interleukin-1β requires 5-lipoxygenase or NADPH oxidase activity. Mol. Cell. Biol.19, 1950–1960.10.1128/MCB.19.3.1950Search in Google Scholar PubMed PubMed Central

Bonizzi, G. and Karin, M. (2004). The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol.25, 280–288.10.1016/j.it.2004.03.008Search in Google Scholar PubMed

Boveris, A., Oshino, N., and Chance, B. (1972). The cellular production of hydrogen peroxide. Biochem. J.128, 617–630.10.1042/bj1280617Search in Google Scholar PubMed PubMed Central

Chance, B., Sies, H., and Boveris, A. (1979). Hydroperoxide metabolism in mammalian organs. Physiol. Rev.59, 527–605.10.1152/physrev.1979.59.3.527Search in Google Scholar PubMed

Chandel, N.S., Maltepe, E., Goldwasser, E., Mathieu, C.E., Simon, M.C., and Schumacker, P.T. (1998). Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc. Natl. Acad. Sci. USA95, 11715–11720.10.1073/pnas.95.20.11715Search in Google Scholar PubMed PubMed Central

Ciechanover, A. (1998). The ubiquitin-proteasome pathway: on protein death and cell life. EMBO J.17, 7151–7160.10.1093/emboj/17.24.7151Search in Google Scholar PubMed PubMed Central

Ciechanover, A. and Schwartz, A.L. (2004). The ubiquitin system: pathogenesis of human diseases and drug targeting. Biochim. Biophys. Acta1695, 3–17.10.1016/j.bbamcr.2004.09.018Search in Google Scholar PubMed

Cleeter, M.W., Cooper, J.M., Darley-Usmar, V.M., Moncada, S., and Schapira, A.H. (1994). Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett.345, 50–54.10.1016/0014-5793(94)00424-2Search in Google Scholar

Cullinan, S.B., Gordan, J.D., Jin, J., Harper, J.W., and Diehl, J.A. (2004). 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, 8477–8486.10.1128/MCB.24.19.8477-8486.2004Search in Google Scholar

Dinkova-Kostova, A.T., Holtzclaw, W.D., Cole, R.N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., and Talalay, P. (2002). 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. USA99, 11908–11913.10.1073/pnas.172398899Search in Google Scholar

Droge, W. (2002). Oxidative stress and aging. Adv. Exp. Med. Biol.543, 191–200.Search in Google Scholar

Eggler, A.L., Liu, G., Pezzuto, J.M., van Breemen, R.B., and Mesecar, A.D. (2005). Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc. Natl. Acad. Sci. USA102, 10070–10075.10.1073/pnas.0502402102Search in Google Scholar

Fandrey, J., Frede, S., and Jelkmann, W. (1994). Role of hydrogen peroxide in hypoxia-induced erythropoietin production. Biochem. J.303, 507–510.10.1042/bj3030507Search in Google Scholar

Fridlyand, L.E. and Philipson, L.H. (2006). Oxidative reactive species in cell injury: mechanisms in diabetes mellitus and therapeutic approaches. Ann. N.Y. Acad. Sci.1066, 136–151.Search in Google Scholar

Furukawa, M., and Xiong, Y. (2005). BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol. Cell. Biol.25, 162–171.10.1128/MCB.25.1.162-171.2005Search in Google Scholar

Gerald, D., Berra, E., Frapart, Y.M., Chan, D.A., Giaccia, A.J., Mansuy, D., Pouyssegur, J., Yaniv, M., and Mechta-Grigoriou, F. (2004). JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell118, 781–794.10.1016/j.cell.2004.08.025Search in Google Scholar

Guardavaccaro, D., Kudo, Y., Boulaire, J., Barchi, M., Busino, L., Donzelli, M., Margottin-Goguet, F., Jackson, P.K., Yamasaki, L., and Pagano, M. (2003). Control of meiotic and mitotic progression by the F box protein β-Trcp1 in vivo. Dev. Cell4, 799–812.10.1016/S1534-5807(03)00154-0Search in Google Scholar

Hagen, T., Taylor, C.T., Lam, F., and Moncada, S. (2003). Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1α. Science302, 1975–1978.10.1126/science.1088805Search in Google Scholar PubMed

Halliwell, B. and Gutteridge, J.M.C. (1989). Free Radicals in Biology and Medicine, 2nd edition (Oxford, UK: Clarendon Press).Search in Google Scholar

Hayden, M.S. and Ghosh, S. (2004). Signaling to NF-κB. Genes Dev.18, 2195–2224.10.1101/gad.1228704Search in Google Scholar PubMed

Hershko, A. and Ciechanover, A. (1998). The ubiquitin system. Annu. Rev. Biochem.67, 425–479.10.1146/annurev.biochem.67.1.425Search in Google Scholar

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

Hirota, K., and Semenza, G.L. (2001). Rac1 activity is required for the activation of hypoxia-inducible factor 1. J. Biol. Chem.276, 21166–21172.10.1074/jbc.M100677200Search in Google Scholar

Hirsila, M., Koivunen, P., Gunzler, V., Kivirikko, K.I., and Myllyharju, J. (2003). Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem.278, 30772–30780.10.1074/jbc.M304982200Search in Google Scholar

Huibregtse, J.M., Scheffner, M., Beaudenon, S., and Howley, P.M. (1995). A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc. Natl. Acad. Sci. USA92, 2563–2567.10.1073/pnas.92.7.2563Search in Google Scholar

Ishii, T., Itoh, K., Takahashi, S., Sato, H., Yanagawa, T., Katoh, Y., Bannai, S., and Yamamoto, M. (2000). Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J. Biol. Chem.275, 16023–16029.10.1074/jbc.275.21.16023Search in Google Scholar

Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, K., Igarashi, K., Engel, J.D., and Yamamoto, M. (1999). Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev.13, 76–86.10.1101/gad.13.1.76Search in Google Scholar

Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J.M., Lane, W.S., and Kaelin, W.G. Jr. (2001). HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O₂ sensing. Science292, 464–468.10.1126/science.1059817Search in Google Scholar

Jaakkola, P., Mole, D.R., Tian, Y.M., Wilson, M.I., Gielbert, J., Gaskell, S.J., Kriegsheim, A.V., Hebestreit, H.F., Mukherji, M., Schofield, C.J., et al. (2001). Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O₂-regulated prolyl hydroxylation. Science292, 468–472.10.1126/science.1059796Search in Google Scholar

Jackson, P.K., Eldridge, A.G., Freed, E., Furstenthal, L., Hsu, J.Y., Kaiser, B.K., and Reimann, J.D. (2000). The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol.10, 429–439.10.1016/S0962-8924(00)01834-1Search in Google Scholar

Jiang, B.H., Semenza, G.L., Bauer, C., and Marti, H.H. (1996). Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O₂ tension. Am. J. Physiol.271, C1172–C1180.10.1152/ajpcell.1996.271.4.C1172Search in Google Scholar PubMed

Johar, D., Roth, J.C., Bay, G.H., Walker, J.N., Kroczak, T.J., and Los, M. (2004). Inflammatory response, reactive oxygen species, programmed (necrotic-like and apoptotic) cell death and cancer. Rocz. Akad. Med. Bialymst.49, 31–39.Search in Google Scholar

Kaelin, W.G. Jr. (2005). The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem. Biophys. Res. Commun.338, 627–638.10.1016/j.bbrc.2005.08.165Search in Google Scholar

Karapetian, R.N., Evstafieva, A.G., Abaeva, I.S., Chichkova, N.V., Filonov, G.S., Rubtsov, Y.P., Sukhacheva, E.A., Melnikov, S.V., Schneider, U., Wanker, E.E., and Vartapetian, A.B. (2005). Nuclear oncoprotein prothymosin α is a partner of Keap1: implications for expression of oxidative stress-protecting genes. Mol. Cell. Biol.25, 1089–1099.10.1128/MCB.25.3.1089-1099.2005Search in Google Scholar

Katoh, Y., Iida, K., Kang, M.-I., Kobayashi, A., Mizukami, M., Tong, K.I., McMahon, M., Hayes, J.D., Itoh, K., and Yamamoto, M. (2005). Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch. Biochem. Biophys.433, 342–350.10.1016/j.abb.2004.10.012Search in Google Scholar

Kim, W., and Kaelin, W.G. Jr. (2003). The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer. Curr. Opin. Genet. Dev.13, 55–60.10.1016/S0959-437X(02)00010-2Search in Google Scholar

Kobayashi, M., Itoh, K., Suzuki, T., Osanai, H., Nishikawa, K., Katoh, Y., Takagi. Y., and Yamamoto, M. (2002). Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system. Genes Cells7, 807–820.10.1046/j.1365-2443.2002.00561.xSearch in Google Scholar PubMed

Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., and Yamamoto, M. (2004). Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol.24, 7130–7139.10.1128/MCB.24.16.7130-7139.2004Search in Google Scholar PubMed PubMed Central

Kobayashi, A., Kang, M.-I., Watai, Y., Tong, K.I., Shibata, T., Uchida, K., and Yamamoto, M. (2006). Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol. Cell. Biol.26, 221–229.10.1128/MCB.26.1.221-229.2006Search in Google Scholar PubMed PubMed Central

Kudo, N., Taoka, H., Toda, T., Yoshida, M., and Horinouchi, S. (1999). A novel nuclear export signal sensitive to oxidative stress in the fission yeast transcription factor Pap1. J. Biol. Chem.274, 15151–15158.10.1074/jbc.274.21.15151Search in Google Scholar PubMed

Lando, D., Peet, D.J., Whelan, D.A., Gorman, J.J., and Whitelaw, M.L. (2002). Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science295, 858–861.10.1126/science.1068592Search in Google Scholar PubMed

Li, W., Yu, S.W., Kong, A.N. (2006). Nrf2 possesses a redox-sensitive NES in the Neh5 transactivation domain. J. Biol. Chem., Epub ahead of print (DOI 10.1074/jbc.M602746200).Search in Google Scholar

McMahon, M., Thomas, N., Itoh, K., Yamamoto, M., and Hayes, J.D. (2004). 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, 31556–31567.10.1074/jbc.M403061200Search in Google Scholar PubMed

Meyer, M., Schreck, R., and Baeuerle, P.A. (1993). H₂O₂ and antioxidants have opposite effects on activation of NF-κB and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J.12, 2005–2015.10.1002/j.1460-2075.1993.tb05850.xSearch in Google Scholar

Mogensen, T.H. and Paludan, S.R. (2001). Molecular pathways in virus-induced cytokine production. Microbiol. Mol. Biol. Rev.65, 131–150.10.1128/MMBR.65.1.131-150.2001Search in Google Scholar

Moncada, S. and Erusalimsky, J.D. (2002). Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nat. Rev. Mol. Cell. Biol.3, 214–220.10.1038/nrm762Search in Google Scholar

Motohashi, H. and Yamamoto, M. (2004). Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol. Med.10, 549–557.10.1016/j.molmed.2004.09.003Search in Google Scholar

Nguyen, T., Sherratt, P.J., Nioi, P., Yang, C.S., and Pickett, C.B. (2005). Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J. Biol. Chem.280, 32485–32492.10.1074/jbc.M503074200Search in Google Scholar

Nicholls, A., Sharp, K.A., and Honig, B. (1991). Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins11, 281–296.10.1002/prot.340110407Search in Google Scholar

Orlicky, S., Tang, X., Willems, A., Tyers, M., and Sicheri, F. (2003). Structural basis for phospho-dependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell112, 243–256.10.1016/S0092-8674(03)00034-5Search in Google Scholar

Padmanabhan, B., Tong, K.I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., and Yamamoto, M. (2006). Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol. Cell21, 689–700.10.1016/j.molcel.2006.01.013Search in Google Scholar PubMed

Palacios-Callender, M., Quintero, M., Hollis, V.S., Springett, R.J., and Moncada, S. (2004) Endogenous NO regulates superoxide production at low oxygen concentrations by modifying the redox state of cytochrome c oxidase. Proc. Natl. Acad. Sci. USA101, 7630–7635.10.1073/pnas.0401723101Search in Google Scholar PubMed PubMed Central

Petroski, M.D. and Deshaies, R.J. (2005). Function and regulation of cullin-RING ubiquitin ligases. Nat. Rev. Mol. Cell Biol.6, 9–20.10.1038/nrm1547Search in Google Scholar PubMed

Pintard, L., Willems, A., and Peter, M. (2004). Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family. EMBO J.21, 1681–1687.10.1038/sj.emboj.7600186Search in Google Scholar

Poderoso, J.J., Carreras, M.C., Lisdero, C., Riobo, N., Schopfer, F., and Boveris, A. (1996). Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles. Arch. Biochem. Biophys.328, 85–92.10.1006/abbi.1996.0146Search in Google Scholar

Rathmell, W.K., Acs, G., Simon, M.C., and Vaughn, D.J. (2004). HIF transcription factor expression and induction of hypoxic response genes in a retroperitoneal angiosarcoma. Anticancer Res.24, 167–169.Search in Google Scholar

Safran, M. and Kaelin, W.G. Jr. (2003). HIF hydroxylation and the mammalian oxygen-sensing pathway. J. Clin. Invest.111, 779–783.10.1172/JCI200318181Search in Google Scholar

Schlesinger, D.H., Goldstein, G., and Niall, H.D. (1975). The complete amino acid sequence of ubiquitin, an adenylate cyclase stimulating polypeptide probably universal in living cells. Biochemistry14, 2214–2218.10.1021/bi00681a026Search in Google Scholar

Schreck, R. and Baeuerle, P.A. (1991). A role for oxygen radicals as second messengers. Trends Cell Biol.1, 39–42.10.1016/0962-8924(91)90072-HSearch in Google Scholar

Shih, A.Y., Imbeault, S., Barakauskas, V., Erb, H., Jiang, L., Li, P., and Murphy, T.H. (2005). Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J. Biol. Chem.280, 22925–22936.10.1074/jbc.M414635200Search in Google Scholar PubMed

Sies, H. (1993). Strategies of antioxidant defense. Eur. J. Biochem.215, 213–219.10.1111/j.1432-1033.1993.tb18025.xSearch in Google Scholar PubMed

Snyder, G.H., Cennerazzo, M.J., Karalis, A.J., and Field, D. (1981). Electrostatic influence of local cysteine environments on disulfide exchange kinetics. Biochemistry20, 6509–6519.10.1021/bi00526a001Search in Google Scholar PubMed

Stogios, P.J. and Prive, G.G. (2004). The BACK domain in BTB-kelch proteins. Trends Biochem. Sci.29, 634–637.10.1016/j.tibs.2004.10.003Search in Google Scholar PubMed

Stogios, P.J., Downs, G.S., Jauhal, J.J., Nandra, S.K., and Prive, G.G. (2005). Sequence and structural analysis of BTB domain proteins. Genome Biol.6, R82–99.10.1186/gb-2005-6-10-r82Search in Google Scholar PubMed PubMed Central

Sulciner, D.J., Irani, K., Yu, Z.X., Ferrans, V.J., Goldschmidt-Clermont, P., and Finkel, T. (1996). Rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-κB activation. Mol. Cell. Biol.16, 7115–7121.10.1128/MCB.16.12.7115Search in Google Scholar

Suzuki, H., Chiba, T., Suzuki, T., Fujita, T., Ikenoue, T., Omata, M., Furuichi, K., Shikama, H., and Tanaka, K. (2000). Homodimer of two F-box proteins βTrCP1 or βTrCP2 binds to IκBα for signal-dependent ubiquitination. J. Biol. Chem.275, 2877–2884.10.1074/jbc.275.4.2877Search in Google Scholar

Tong, K.I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., and 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, 2887–2900.10.1128/MCB.26.8.2887-2900.2006Search in Google Scholar

Turrens, J.F. (2003). Mitochondrial formation of reactive oxygen species. J. Physiol.552, 335–344.10.1113/jphysiol.2003.049478Search in Google Scholar

Velichkova, M. and Hasson, T. (2005). Keap1 regulates the oxidation-sensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Mol. Cell. Biol.25, 4501–4513.10.1128/MCB.25.11.4501-4513.2005Search in Google Scholar

Wakabayashi, N., Itoh, K., Wakabayashi, J., Motohashi, H., Noda, S., Takahashi, S., Imakado, S., Kotsuji, T., Otsuka, F., Roop, D.R., et al. (2003). Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat. Genet.35, 238–245.10.1038/ng1248Search in Google Scholar

Wakabayashi, N., Dinkova-Kostova, A.T., Holtzclaw, W.D., Kang, M.I., Kobayashi, A., Yamamoto, M., Kensler, T.W., and Talalay, P. (2004). 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. USA101, 2040–2045.10.1073/pnas.0307301101Search in Google Scholar

Wu, G., Xu, G., Schulman, B.A., Jeffrey, P.D., Harper, J.W., and Pavletich, N.P. (2003). Structure of a β-TrCP1-Skp1-β-catenin complex: destruction motif binding and lysine specificity of the SCF(β-TrCP1) ubiquitin ligase. Mol. Cell11, 1445–1456.10.1016/S1097-2765(03)00234-XSearch in Google Scholar

Zhang, D.D. and Hannink, M. (2003). 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, 8137–8151.10.1128/MCB.23.22.8137-8151.2003Search in Google Scholar PubMed PubMed Central

Zhang, D.D., Lo, S.C., Cross, J.V., Templeton, D.J., and Hannink, M. (2004). Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol. Cell. Biol.24, 10941–10953.10.1128/MCB.24.24.10941-10953.2004Search in Google Scholar PubMed PubMed Central

Zipper, L.M. and Mulcahy, R.T. (2002). The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J. Biol. Chem.277, 36544–36552.10.1074/jbc.M206530200Search in Google Scholar PubMed