Structural study for understanding the molecular mechanism of ectodomain shedding by ADAM family proteinases

2013 Fiscal Year Final Research Report

• Project/Area Number: 23570156
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: TAKEDA Soichi 独立行政法人国立循環器病研究センター, 研究所, 室長 (80332279)
• Project Period (FY): 2011 – 2013
• Keywords: プロテアーゼ / シグナリング / 構造生物学 / 基質認識機構 / マルチドメイン構造 / X線結晶構造解析 / タンパク質間相互作用 / ディスインテグリン

Research Abstract

ADAM proteinases are mostly type-1 membrane-bound glycoproteins and function as major sheddases for the processing of cell-surface-protein ectodomains, including the latent forms of growth factors and cytokines. ADAMs play key roles in normal development and morphogenesis and are associated with several diseases, including cancer and Alzheimer's disease. There are no consensus amino acid sequences around the sites cleaved by ADAMs and the molecular mechanism how ADAMs recognize the target molecules remains elusive. We focused on several ADAMs from snake venoms for crystallographic studies because snake ADAMs are soluble proteinases without membrane-spanning regions and usually display high specificity for distinct target molecules. Multactivase isolated from Echis multimantus has a prothrombin-activating activity. We have determined a crystal structure of the exosite domain of Multactivase and discussed the molecular mechanism of prothrombin recognition for cleavage by Multactivase.

Research Products

• [Journal Article] 東アジア人特有のP475S変異を持つADAMTS13の立体構造と機能解析 (2013)
  • Author(s): 秋山正志, 武田壮一, 宮田敏行
  • Journal Title: 日本血栓止血学会誌 Volume: 24(6) Pages: 613-618
• [Journal Article] Crystal structure of an ADAMTS13 mutant with the East Asian-specific P475S polymorphism (2013)
  • Author(s): Akiyama M, Nakayama D, Takeda S, Kokame K, Takagi J, Miyata T.
  • Journal Title: J. Thromb. Haemost. Volume: 11 Pages: 1399-1406
  • Peer Reviewed
• [Journal Article] ADAM/ADAMTSファミリープロテアーゼの構造と機能 (2013)
  • Author(s): 武田壮一
  • Journal Title: 臨床検査 Volume: 57(5) Pages: 535-540
• [Journal Article] ADAMTS13研究の最先端 (2012)
  • Author(s): 宮田敏行, 小亀浩市, 秋山正志, 坂野史朗, 中山大輔, 武田壮一
  • Journal Title: 臨床血液 Volume: 53(7) Pages: 672-679
• [Journal Article] Snake venom metalloproteinases : structure, function and relevance to the mammalian ADAM/ADAMTS family proteins (Review article) (2012)
  • Author(s): Takeda S, Takeya H, Iwanaga S.
  • Journal Title: Biochim Biophys Acta Proteins and Proteomics Volume: 1824 Pages: 164-176
  • Peer Reviewed
• [Journal Article] Enzymatic Toxins from Snake Venom : Structural Characterization and Mechanism of Catalysis (Review article) (2011)
  • Author(s): Kang TS, Georgieva D, Genov N, Murakami MT, Sinha M, Kumar RP, Kaur P, Kumar S, Dey S, Sharma S, Vrielink A, Betzel C, Takeda S, Arni RK, Singh TP, Kini RM.
  • Journal Title: FEBS J. Volume: 278 Pages: 4544-4576
  • Peer Reviewed
• [Presentation] Snake venom metalloproteinases; Structure, function and relevance to the mammalian ADAM/ADAMTS family proteins (2012)
  • Author(s): Soichi Takeda
  • Organizer: Concurrent session-34: Structure/Function of Venom, 17th World Congress of the International Society on Toxinology
  • Place of Presentation: Honolulu, Hawaii
  • Year and Date: 20120700
  • Invited
• [Presentation] P475S型ADAMTS13タンパク質の部分立体構造決定 (2011)
  • Author(s): 秋山正志、中山大輔、武田壮一、小亀浩市、高木淳一、宮田敏行
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都国際会館
  • Year and Date: 20110900
• [Presentation] P475S型ADAMTS13の非触媒領域の立体構造決定 (2011)
  • Author(s): 中山大輔, 秋山正志, 武田壮一, 小亀浩市, 高木淳一, 宮田敏行
  • Organizer: 第16回日本病態プロテアーゼ学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 20110800
• [Presentation] Structural basis of factor V recognition by russell's viper venom proteinase RVV-V (2011)
  • Author(s): Daisuke Nakayama, Youssef Ben Ammar, Soichi Takeda.
  • Organizer: XXIII Congress of the International Society of Thrombosis and Haemostasis (ISTH2011)
  • Place of Presentation: Kyoto International Conference Center
  • Year and Date: 20110700
• [Presentation] Structural basis for ADAMTS13 function (2011)
  • Author(s): Masashi Akiyama, Daisuke Nakayama, Soichi Takeda, Koichi Kokame, Junichi Takagi, Toshiyuki Miyata.
  • Organizer: XXIII Congress of the International Society of Thrombosis and Haemostasis (ISTH2011)
  • Place of Presentation: Kyoto International Conference Center
  • Year and Date: 20110700
• [Presentation] Structural basis of coagulation factor V recognition for cleavage by RVV-V
  • Author(s): Soichi Takeda
  • Organizer: International Society of Thrombosis and Hemostasis (ISTH) Meeting, Registry of Exogenous factors, 17th World Congress of the International
• [Book] Russellysin (Book chapter)"In The 3^<rd> edition of Handbook of Proteolytic Enzymes (Rawlings, N. and Salvesen, G. (ed.)) (2013)
  • Author(s): Takeda S.
  • Total Pages: 1051-1053
  • Publisher: Elsevier
• [Book] "Structure-function relationship of the modular domains of the P-III class snake venom metalloproteinases (SVMPs) (Book chapter)"In Handbook of Toxinology, Venom Genomics and Proteomics (Gopalakrishnakone P. (ed.))
  • Author(s): Takeda S.
  • Total Pages: (in press)
  • Publisher: SpringerReference, Springer