Structural biology of mitochondrial quality control regulated by ubiquitin

• Project/Area Number: 16H04750
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Sato Yusuke 東京大学, 定量生命科学研究所, 助教 (50568061)
• Research Collaborator: Okatsu Kei
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: ユビキチン / 結晶構造解析 / パーキンソン病 / マイトファジー / オートファジー / X線結晶構造解析 / ユビキチン鎖 / タンパク質分解 / 構造生物学 / 蛋白質 / ミトコンドリア品質管理 / ミトコンドリア

Outline of Final Research Achievements

Accumulation of damaged mitochondria is reported as one of the factors of parkinsonism. PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin (Ub) ligase parkin are essential for ubiquitylation of damaged mitochondria and subsequent degradation. PINK1 phosphorylates Ser65 of Ub and the Ub-like (UBL) domain of parkin to allosterically relieve the autoinhibition of parkin. On the other hand, USP30 deubiquitinase opposes parkin-mediated Ub-chain formation on mitochondria by preferentially cleaving Lys6-linked Ub chains. In this study, w determined the crystal structures of PINK1 in complex with a nonhydrolyzable ATP analogue and USP30 in complex with Lys6-linked Ub chain.

Academic Significance and Societal Importance of the Research Achievements

社会の高齢化と、それに伴うパーキンソン病患者の増加から、パーキンソン病関連の研究は国内外問わず注目を集めている。パーキンソン病の原因遺伝子産物であるPINK1とParkinによるUb鎖合成と、USP30によるUb鎖除去がミトコンドリア品質管理の制御に関わる。その活性化、および抑制機構は細胞生物学と生化学的手法により示されてきたが、詳細な分子メカニズムについては不明な点も多かった。本研究によるPINK1によるParkin活性化メカニズムや、USP30によるUb鎖除去メカニズムの解明はパーキンソン病の発症の理解をするために重要である。

Research Products

• [Journal Article] Structural basis of guanine nucleotide exchange for Rab11 by SH3BP5 (2019)
  • Author(s): Goto-Ito Sakurako、Morooka Nobukatsu、Yamagata Atsushi、Sato Yusuke、Sato Ken、Fukai Shuya
  • Journal Title: Life Science Alliance Volume: 2 Issue: 2 Pages: e201900297-e201900297
  • DOI: 10.26508/lsa.201900297
  • Peer Reviewed / Open Access
• [Journal Article] Structural basis of ubiquitin recognition by the winged-helix domain of Cockayne syndrome group B protein (2019)
  • Author(s): Takahashi Tomio S、Sato Yusuke、Yamagata Atsushi、Goto-Ito Sakurako、Saijo Masafumi、Fukai Shuya
  • Journal Title: Nucleic Acids Research Volume: 47 Issue: 7 Pages: 3784-3794
  • DOI: 10.1093/nar/gkz081
  • Peer Reviewed / Open Access
• [Journal Article] Structural insights into modulation and selectivity of transsynaptic neurexin?LRRTM interaction (2018)
  • Author(s): Yamagata Atsushi、Goto-Ito Sakurako、Sato Yusuke、Shiroshima Tomoko、Maeda Asami、Watanabe Masahiko、Saitoh Takashi、Maenaka Katsumi、Terada Tohru、Yoshida Tomoyuki、Uemura Takeshi、Fukai Shuya
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 3964-3964
  • DOI: 10.1038/s41467-018-06333-8
  • Peer Reviewed / Open Access
• [Journal Article] Structural insights into ubiquitin phosphorylation by PINK1 (2018)
  • Author(s): Okatsu Kei、Sato Yusuke、Yamano Koji、Matsuda Noriyuki、Negishi Lumi、Takahashi Akiko、Yamagata Atsushi、Goto-Ito Sakurako、Mishima Masaki、Ito Yutaka、Oka Toshihiko、Tanaka Keiji、Fukai Shuya
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 10382-10382
  • DOI: 10.1038/s41598-018-28656-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Crystal structure of the central and the C-terminal RNase domains of colicin D implicated its translocation pathway through inner membrane of target cell (2018)
  • Author(s): Chang Jung-Wei、Sato Yusuke、Ogawa Tetsuhiro、Arakawa Takatoshi、Fukai Shuya、Fushinobu Shinya、Masaki Haruhiko
  • Journal Title: The Journal of Biochemistry Volume: 164 Issue: 5 Pages: 329-339
  • DOI: 10.1093/jb/mvy056
  • NAID: 40021724807
  • Peer Reviewed
• [Journal Article] Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22 (2018)
  • Author(s): Yamagata Atsushi、Miyazaki Yuri、Yokoi Norihiko、Shigematsu Hideki、Sato Yusuke、Goto-Ito Sakurako、Maeda Asami、Goto Teppei、Sanbo Makoto、Hirabayashi Masumi、Shirouzu Mikako、Fukata Yuko、Fukata Masaki、Fukai Shuya
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1546-1546
  • DOI: 10.1038/s41467-018-03947-w
  • Peer Reviewed / Open Access
• [Journal Article] Structural basis of trans-synaptic interactions between PTPδ and SALMs for inducing synapse formation (2018)
  • Author(s): Goto-Ito Sakurako、Yamagata Atsushi、Sato Yusuke、Uemura Takeshi、Shiroshima Tomoko、Maeda Asami、Imai Ayako、Mori Hisashi、Yoshida Tomoyuki、Fukai Shuya
  • Journal Title: Nature Communications Volume: 9 Issue: 1
  • DOI: 10.1038/s41467-017-02417-z
  • Peer Reviewed / Open Access
• [Journal Article] Structural insights into two distinct binding modules for Lys63-linked polyubiquitin chains in RNF168 (2018)
  • Author(s): Takahashi Tomio S.、Hirade Yoshihiro、Toma Aya、Sato Yusuke、Yamagata Atsushi、Goto-Ito Sakurako、Tomita Akiko、Nakada Shinichiro、Fukai Shuya
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 170-170
  • DOI: 10.1038/s41467-017-02345-y
  • Peer Reviewed / Open Access
• [Journal Article] Structural basis for specific cleavage of Lys6-linked polyubiquitin chains by USP30 (2017)
  • Author(s): Sato Yusuke、Okatsu Kei、Saeki Yasushi、Yamano Koji、Matsuda Noriyuki、Kaiho Ai、Yamagata Atsushi、Goto-Ito Sakurako、Ishikawa Minoru、Hashimoto Yuichi、Tanaka Keiji、Fukai Shuya
  • Journal Title: Nature Structural & Molecular Biology Volume: 24 Issue: 11 Pages: 911-919
  • DOI: 10.1038/nsmb.3469
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Structural basis of the interaction between Topoisomerase IIIβ and the TDRD3 auxiliary factor. (2017)
  • Author(s): Goto-Ito S, Yamagata A, Takahashi TS, Sato Y, Fukai S.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 42123-42123
  • DOI: 10.1038/srep42123
  • Peer Reviewed / Open Access
• [Journal Article] Crystal structure of Sec10, a subunit of the exocyst complex (2017)
  • Author(s): Chen J, Yamagata A, Kubota K, Sato Y, Goto-Ito S, Fukai S.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 40909-40909
  • DOI: 10.1038/srep40909
  • Peer Reviewed / Open Access
• [Journal Article] Distinct Roles for the N- and C-terminal Regions of M-Sec in Plasma Membrane Deformation during Tunneling Nanotube Formation. (2016)
  • Author(s): Kimura S, Yamashita M, Yamakami-Kimura M, Sato Y, Yamagata A, Kobashigawa Y, Inagaki F, Amada T, Hase K, Iwanaga T, Ohno H, Fukai S.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 33548-33548
  • DOI: 10.1038/srep33548
  • NAID: 120005855947
  • Peer Reviewed / Open Access
• [Presentation] Structural insights into ubiquitin recognition and Ufd1 interaction of Npl4 (2019)
  • Author(s): Sato Y, Tsuchiya H, Tanaka K, Saeki Y, Fukai S
  • Organizer: Cold Spring Harbor meeting: Ubiquitins, Autophagy & Disease
  • Int'l Joint Research
• [Presentation] ユビキチン鎖が制御する複雑なシステムの構造基盤 (2018)
  • Author(s): 佐藤裕介，高橋富雄，深井周也
  • Organizer: 日本生化学会大会