New Paradigm for molecular mechanism of amyloid formation and disaggregation

• Project/Area Number: 15H04345
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Tanaka Motomasa 国立研究開発法人理化学研究所, 脳科学総合研究センター, チームリーダー (40321781)
• Co-Investigator(Renkei-kenkyūsha): KUWATA Kazuo 岐阜大学, 連合創薬医療情報研究科, 教授 (00170142) ; KONNO Hiroki 金沢大学, バイオAFM先端研究センター, 准教授 (80419267)
• Research Collaborator: NAKAGAWA Yoshiko ; Shen Chih-hao
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: アミロイド / 神経変性疾患 / 精神疾患 / タンパク質 / プリオン / シャペロン / 蛋白質 / 酵母プリオン / 脳神経疾患 / 分子シャペロン

Outline of Final Research Achievements

Self-propagating β-sheet-rich fibrillar protein aggregates, amyloid fibers, are often associated with cellular dysfunction and disease. Distinct amyloid conformations dictate different physiological consequences, such as cellular toxicity. However, the origin of the diversity of amyloid conformation remains unknown. Here, we suggest that altered conformational equilibrium in natively disordered monomeric proteins leads to the adaptation of alternate amyloid conformations that have different phenotypic effects. We performed a comprehensive high-resolution structural analysis of Sup35NM, an N-terminal fragment of the Sup35 yeast prion protein, and found that monomeric Sup35NM harbored latent local compact structures despite its overall disordered conformation. In addition, we found that the chaperone machinery has distinct remodeling activity to different prion strain conformations of Sup35.

Research Products

• [Int'l Joint Research] デュッセルドルフ大学 物理生物学研究所(ドイツ)
• [Journal Article] Molecular basis for diversification of yeast prion strain conformation (2018)
  • Author(s): Ohhashi Yumiko、Yamaguchi Yoshiki、Kurahashi Hiroshi、Kamatari Yuji O.、Sugiyama Shinju、Uluca Boran、Piechatzek Timo、Komi Yusuke、Shida Toshinobu、M?ller Henrik、Hanashima Shinya、Heise Henrike、Kuwata Kazuo、Tanaka Motomasa
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 10 Pages: 2389-2394
  • DOI: 10.1073/pnas.1715483115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Molecular basis for Hsp104-mediated prion propagation in yeast (2016)
  • Author(s): Yoshiko Nakagawa, Hideki Taguchi, Motomasa Tanaka
  • Organizer: 第54回日本生物物理学会大会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2016-11-25
• [Presentation] プリオン様タンパク質の感染性の本体とその生成分子機構の解明 (2016)
  • Author(s): 田中元雅、大橋祐美子、志田俊信
  • Organizer: 第21回日本神経感染症学会
  • Place of Presentation: 金沢東急ホテル
  • Year and Date: 2016-10-21
  • Invited
• [Presentation] Latent structural variation in a yeast prion monomer determines strain phenotypes (2016)
  • Author(s): Motomasa Tanaka, Yumiko Ohhashi, Yoshiki Yamaguchi, Yuji O. Kamatari, Kazuo Kuwata
  • Organizer: PRION2016
  • Place of Presentation: Hitotsubashi Hall, National Center of Sciences Building
  • Year and Date: 2016-05-10
  • Int'l Joint Research
• [Remarks] アミロイド構造の多様性の原因解明
  • URL: http://www.riken.jp/pr/press/2018/20180322_1/