hree-dimensional Structure of Nrf2-Maf transcription factor complex mediating the induction of phase II detoxifying enzymes

• Project/Area Number: 21510066
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: Tohoku University
• Principal Investigator: KUROKAWA Hirofumi 東北大学, 大学院・医学系研究科, 講師 (80359546)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: タンパク質 / 結晶構造解析 / 毒性化学物質 / 酸化ストレス / Keap1 / Keapl

Research Abstract

Nrf2 and Maf transcription factors form hetero dimmer and mediate the induction of phase II detoxifying enzymes in response to oxidative stress. We determined the crystal structure of Maf dimmer in complex with its cognate DNA and revealed the unique DNA recognition mechanism by Maf. We also determined the 3D structure of Keap1, a negative regulator of Nrf2 transcription factor in response to oxidative stress, by using single particle electron microscopy. Keap1 consists of two large spheres connected by stem region. In addition we found that p62, a selective autophagy substrate, competitively binds to Keap1 and activates Nrf2. Crystal structure of p62-Keap1 complex has been solved and showed that p62 competitively binds to Nrf2 binding pocket of Keap1.

Research Products

• [Journal Article] 酸化ストレスセンサー分子KEAP1阻害剤 (2011)
  • Author(s): 黒河博文、山本雅之
  • Journal Title: 血管医学 Volume: 12 Pages: 23-30
• [Journal Article] The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 (2010)
  • Author(s): Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y. S., Ueno, I., Sakamoto, A., Tong, K. I., Kim, M., Nishito, Y., Iemura, S., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka, K., and Yamamoto, M
  • Journal Title: Nature Cell Biology Volume: 12巻 Pages: 213-223
  • Peer Reviewed
• [Journal Article] Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains (2010)
  • Author(s): Ogura, T., Tong, K. I., Mio, K., Maruyama, Y., Kurokawa, H., Sato, C., and Yamamoto, M.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 107巻 Pages: 2842-2847
  • Peer Reviewed
• [Journal Article] Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. (2010)
  • Author(s): Ogura, T., Tong, K.I., Mio, K., Maruyama, Y., Kurokawa, H., Sato, C., Yamamoto, M.
  • Journal Title: Proc Natl Acad Sci U S A 107 Pages: 2842-2847
  • Peer Reviewed
• [Journal Article] The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. (2010)
  • Author(s): Komatsu, M., H.Kurokawa, et al.
  • Journal Title: Nature Cell Biology 12 Pages: 213-223
  • Peer Reviewed
• [Journal Article] Structural basis of alternative DNA recognition by Maf transcription factors (2009)
  • Author(s): Kurokawa, H., Motohashi, H., Sueno, S., Kimura, M., Takagawa, H., Kanno, Y., Yamamoto, M., and Tanaka, T
  • Journal Title: Molecular and Cellular Biology Volume: 29巻 Pages: 6232-6244
  • Peer Reviewed
• [Journal Article] Structural basis of alternative DNA recognition by Maf transcription factors (2009)
  • Author(s): Kurokawa, H., Motohashi, H., Sueno, S., Kimura, M., Takagawa, H., Kanno, Y., Yamamoto, M., Tanaka, T
  • Journal Title: Molecular and Cellular Biology 29 Pages: 6232-6244
  • Peer Reviewed
• [Presentation] 発癌性物質や酸化ストレスに応答する生体防御系センサーの構造基盤 (2012)
  • Author(s): 黒河博文, 本橋ほづみ, 佐藤主税、山本雅之
  • Organizer: 平成23年度ターゲットタンパク研究プログラム公開シンポジウム
  • Place of Presentation: 学術総合センター
  • Year and Date: 2012-03-12
• [Presentation] 発癌性物質や酸化ストレスに応答する生体防御系センサーの構造基盤 (2011)
  • Author(s): 黒河博文, 本橋ほづみ, 佐藤主税、山本雅之
  • Organizer: 平成22年度ターゲットタンパク研究プログラム公開シンポジウム
  • Place of Presentation: 東京大学安田講堂
  • Year and Date: 2011-03-11
• [Remarks]
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/index.html
• [Remarks]
  • URL: http://www.dmbc.med.tohoku.ac.jp/official/index.html
• [Remarks]
  • URL: http://db.tohoku.ac.jp/whois/detail/24867098a4ed1bcfcd608ca38c1b54e8.html