Structural Biology of Innate Immunity

2009 Fiscal Year Final Research Report

• Project/Area Number: 17109002
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Hokkaido University
• Principal Investigator: INAGAKI Fuyuhiko Hokkaido University, 大学院・薬学研究院, 教授 (70011757)
• Co-Investigator(Kenkyū-buntansha): NODA Nobuo 北海道大学, 大学院・薬学研究院, 講師 (40396297) ; OGURA Kenji 北海道大学, 大学院・薬学研究院, 助教 (50270682) ; HORIUCHI Masataka 北海道大学, 大学院・薬学研究院, 助教 (90322825)
• Project Period (FY): 2005 – 2009
• Keywords: 自然免疫 / 好中球活性酸素発生系 / NADPH酸化酵素 / SH3ドメイン / PXドメイン / インターフェロン産生系 / TLR / TIR / IRF-3 / リン酸化 / Βgrp / β1-3グルカン

Research Abstract

(1)We elucidated the molecular mechanism for tethering p^<47> and p^<40> to cyt b558 or membrane on the structural basis.
(2)We found that IRF-3 is phosphorylated by IKKi at Ser386 and form a homodimer to bind CBP/p300in vitro and produces type Iinterferons.
(3)RIG-I like receptor family proteins (RLR) play essential roles to recognize double stranded RNA (dsRNA) in cytosol. We found that the C terminal domain of RLR recognizes viral specific dsRNA. Wedetermined the structure of C-terminal domain of RLR and discussed the specific interaction with viral specific dsRNA.
(4)dsRNA and LPS bind to TLR3 and TLR4, respectively to activate downstream signaling to producetype 1 interferons. Here, we determined the structure of TIR domains of TRIF and TRAM andelucidated their oligomerization process which is essential for down stream signaling.
(5)We elucidated the recognition mechanism of β1-3 glucan by βGRP from Bombyx Mori.

Research Products

• [Journal Article] Solution structure of the silkworm βGRP/GNBP3 N-terminal domain reveals the mechanism for β-1, 3-glucan-specific recognition. (2009)
  • Author(s): Takahasi K., Ochiai M., Horiuchi M., Kumeta H., Ogura K., Ashida M., Inagaki F.
  • Journal Title: Proc Natl Acad Sci U S A 106 Pages: 11679-11684
  • Peer Reviewed
• [Journal Article] The Domain Organization of p67phox, a Protein Required for Activation of the Superoxide-Producing NADPH Oxidase in Phagocytes. (2009)
  • Author(s): Yuzawa S., Miyano K., Honbou K., Inagaki F., Sumimoto H.
  • Journal Title: J Innate Immun. 1 Pages: 543-555
  • Peer Reviewed
• [Journal Article] Nonself RNA-Sensing Mechanism of RIG-I Helicase and Activation of Antiviral Immune Responses. (2008)
  • Author(s): Takahasi K., Yoneyama M., Nishihori T., Hirai R., Kumeta H., Narita R., Gale M. Jr, Inagaki F, Fujita T.
  • Journal Title: Mol. Cell 29 Pages: 428-440
  • Peer Reviewed
• [Journal Article] Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding. (2007)
  • Author(s): Honbou K., Minakami R., Yuzawa S., Takeya R., Suzuki N.N., Kamakura S., Sumimoto H., Inagaki F.
  • Journal Title: EMBO J 26 Pages: 1176-1186
  • Peer Reviewed
• [Journal Article] NMR Solution Structure of the Tandem Src Homology 3 Domains p47phox Complexed with a p22phox-derived Proline-rich Peptide. (2006)
  • Author(s): Ogura K., Nobuhisa I., Yuzawa S., Takeya R., Torikai S., Saikawa K., Sumimoto H., Inagaki F.
  • Journal Title: J. Biol. Chem 281 Pages: 3660-3668
  • Peer Reviewed
• [Journal Article] Activation of the superoxide-producing phagocyte NADPH oxidase requires co-operation between the tandem SH3 domains of p47phox in recognition of a polyproline type II helix and an adjacent alpha-helix of p22phox. (2006)
  • Author(s): Nobuhisa I., Takeya R., Ogura K., Ueno N., Kohda D., Inagaki F. Sumimoto H.
  • Journal Title: Biochem. J 396 Pages: 183-192
  • Peer Reviewed
• [Journal Article] Solution structures of cytosolic RNA sensor MDA5 and LGP2 C-terminal domains: identification of the RNA recognition loop in RIG-I-like receptors.
  • Author(s): Takahasi K., Kumeta H., Tsuduki N., Narita R., Shigemoto T., Hirai R., Yoneyama M., Horiuchi M., Ogura K., Fujita T., Inagaki F.
  • Journal Title: J Biol Chem Pages: 17465-17474
• [Presentation] TICAM-1およびTICAM-2 TIRドメインの溶液構造 (2009)
  • Author(s): 久米田博之
  • Organizer: 第48回NMR討論会
  • Place of Presentation: 九州大学馬出病院キャンパス医学部百年講堂
  • Year and Date: 20091110-20091112
• [Presentation] Soft interaction in phagocyte oxidation system (2009)
  • Author(s): 稲垣冬彦
  • Organizer: International Symposium on Molecular Soft Interactions in Biological Systems
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 20090122-20090123
• [Presentation] Structural Basis for the regulation of Phagocyte NADPH Oxidase Activity (2007)
  • Author(s): Fuyuhiko Inagaki
  • Organizer: The 16th ISMAR conference
  • Place of Presentation: Kenting, Taiwan
  • Year and Date: 20071014-20071019