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2000 Fiscal Year Final Research Report Summary

Structure-Function Relationships of Proteins Modulating Platelet Adhesion and Aggregation

Research Project

Project/Area Number 09480155
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Structural biochemistry
Research InstitutionFujita Health University

Principal Investigator

TITANI Koiti  Inst.for Comprehensive Med.Sci., Fujita Health University Research Fellow, 総合医科学研究所, 研究員 (60179942)

Co-Investigator(Kenkyū-buntansha) HAMAKO Jiharu  Fujita Health University College, Associate Professor, 衛生技術科, 助教授 (80180933)
HAYASHI Nobuhiro  Inst.for Comprehensive Med.Sci., Fujita Health University Research Associate, 総合医科学研究所, 助手 (80267955)
MATSUI Taei  Inst.for Comprehensive Med.Sci., Fujita Health University Assistant Professor, 総合医科学研究所, 講師 (90183946)
FUJIMURA Yoshihiro  Nara Medical University, Professor, 輸血部, 教授 (80118033)
Project Period (FY) 1997 – 2000
Keywordsvon Willebrand factor / Snake venom protein / Platelet aggregation / Bitiscetin / Kaouthiagin / Metalloproteinase / Disintegrin / Primary structure
Research Abstract

1) Studies on the isolation and structure-function relationship of snake venom proteins modulating interaction between von Willebrand factor (vWF) and platelets. We have searched, identified and structurally characterized novel snake venom proteins that modulate platelet adhesion and aggregation by interacting with vWF.a) We screened. vWF-binding proteins from 19 species of snake venoms and discovered "bitiscetin", a novel vWF-modulating protein from the venom of Bitis arietans, and "kaouthiagin", a vWF-cleaving metalloproteinase from the venom of Naja kaouthia. We purified the two proteins and determined their complete amino acid sequences. Since the sequence of bitiscetin was not highly homologous to that of botrocetin with a similar activity, we expressed many mutants of A-1 loop of vWF, which binds to it, to identify residues interacting with bitiscetin. The results indicated that bitiscetin interacts with a site not identical but very close to that interacts with botrocetin. Kaout … More hiagin was shown to be composed of metalloproteinase, disintegrin-like and Cys-rich domains. Interestingly, the Cys-rich domain contained a RGD sequence. We demonstrated that both the disintegrin-like and Cys-rich domains have the disintegrin activity using synthetic cyclic peptides. b) We purified a protein termed "mamushigin" from the venom of Agkistrodon halys blomhoffii (Japanese "mamushi") which binds to platelet GPIb to induce the aggregation. We isolated the cDNA clones encoding the α and β chains from the library and predicted the complete amino acid sequences of both the chains. From the same venom, we also isolated and determined the complete amino acid sequence of a serine protease termed halystase which releases bradykinin from kininogen in human plasma.
2) Origin of plasma vWF with ABO blood group antigens. vWF is a unique plasma protein with the blood group antigens. Since those antigens on human plasma vWF are not changed to those of the donors after ABO-mismatched bone marrow transplantation, we concluded that plasma vWF with the blood groups is derived from endothelial cells, but not from megakaryocytes (platelets). Less

  • Research Products

    (47 results)

All Other

All Publications (47 results)

  • [Publications] Matsui,T. et al.: "Interaction of von Willebrand Factor with the Extra- cellular Matrix and Glycocalicin under Static Conditions."J.Biochem.. 121. 376-381 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsui,T. et al.: "Kaouthiagin, a Matalloproteinase Purified from Naja Kauthis Cobra Venom, Specifically Binds to and Cleaves von Willebrand Factor (Abstract)."Blood. 90. 466a (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Miura,S. et al.: "Dimeric Structure of von Willebrand Factor Al-loop Region is Required to Show a Complete Inhibition on High-shear Stress Induced Platelet Aggregation (Abatract)."Blood. 90. 466a (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsui,T. et al.: "Complete Amino Acid Sequence of Bitiscetin, a Novel von Willebrand Factor Modulator Protein, Purified from Snake Venom of Bitis arietans."Res.Commun.Cell Mol.Biol.. 1. 271-284 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 千谷晃一,林宣宏: "蛋白質構造研究の新しい動向."臨床病理. 46. 450-455 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsui,T. et al.: "Purification and Amino Acid Sequence of Halystase from Snake Venom of Agkistrodon halys blomhoffi, a Serine Protease Specifically Cleaving Fibrinogen and Kininogen."Eur.J.Biochem.. 252. 569-575 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sakurai,Y. et al.: "The cDNA Cloning and Molecular Characterization of a Novel Snake Venom Platelet Glycoprotein Ib-binding Protein, Mamushigin."Thromb.Haemost.. 79. 1199-1207 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hamako,J. et al.: "Purification and characterization of Kaouthiagin, a von Wilebrand Factor-Binding and-Cleaving Metalloproteinase from Naja Kauthia Cobra Venom."Thromb.Haemost.. 80. 499-505 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Makita,K. et al.: "Placental ecto-ATP Diphosphohydrolase : Its Structural Feature Distinct from CD39, Localization, and Inhibition on Shear-induced Platelet Aggregation."Int.J.Hematol.. 68. 297-310 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Miura,S. et al.: "Total Inhibition of High Shear Stress Induced Platelet Aggregation by Homodimeric von Willebrand Factor Al-loop Fragments."Br.J.Haematol.. 105. 1092-1100 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsui,T. et al.: "ABO Blood Group Antigens on Human Plasma von Willebrand Factor after ABO-Mismatched Bone Marrow Transplantation."Blood. 94. 2895-2900 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsumoto,M. et al.: "The cDNA Cloning of Human Placental Ecto-ATP Diphophohydrolases I and II."FEBS Letts.. 453. 335-340 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsui,T. et al.: "Snake Venom Proteases Affecting Hemostasis and Thrombosis (Review)."Biochim.Biophys.Acta. 1477. 146-156 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 松井太衛 他: "立体構造から見たフォン・ビルブランド因子(vWF)の機能ドメイン。"日本血栓止血学会誌. 11. 268-275 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yagi,H., et al.: "Plasmas with Upshaw-Schulman Syndrome, a Congenital Deficiency of von Willebrand Factor-cleaving Protease, Augment the Aggregation of Normal Washed Platelets under High-shear-stress (Abstract)."Blood. 96. (11-S-1),630a. (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsumoto,M., et al.: "Liver Transplantation Rescues a Dificient State of von Willebrand factor-cleaving Protease Activity in Patients with Liver Cirrhosis due to Congenital Biliary Atresia (Abstract)."Blood. 96. (11-S-1),636a. (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takatsuka,H. et al.: "Molecular Characterization of L-Amino Acid Oxidase from Agkistrodon halys blomhoffi with Special Reference to Platelet Aggregation."Biochim.Biophys.Acta. 1544. 207-277 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yagi,H. et al.: "Enhanced Low Shear Stress Induced Platelet Aggregation by Shiga-like Toxin 1 Purified from Escherichia coli O157."Am.J.Hematol.. 66. 105-115 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsui,T. et al.: "Comparative Study of Blood Group-recognizing Lectins toward ABO Blood Group Antigens on Neoglycoproteins, Glycoproteins and Complex-type Oligosaccharides"Biochim.Biophys.Acta. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kinoshita,S. et al.: "Upshaw-Schulman Syndrome Revisited : A Concept of Congenital Thrombotic Thrombocytopenic Purpura."Int.J.Hematol.. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ito,M. et al.: "Complete Amino Acid Sequence of Kaouthiagin, a Novel Cobra Venom Metalloproteinase with Two Disintegrin-like Sequences."Biochemistry. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 松井太衛: "血小板血栓形成の分子機構(藤村吉博 編)IV.von Willebrand 因子(vWF):4.コラーゲン結合ドメイン"ライフサイエンス社、東京. 253 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 千谷晃一 他: "血小板血栓形成の分子機構(藤村吉博 編)V.血小板凝集を調節する蛇毒蛋白質2.vWF-GPIb軸の相互作用に影響を及ぼす蛇毒蛋白質の構造と機能"ライフサイエンス社、東京. 253 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsui,T.,and Titani,K.: "Lectin Methods and Protocols, Methods in Molecular Medicine Vol.9, (Rhodes, J.M., and Milton, J.D., eds.) 19.ABO(H) Blood Group Expression on Circulating Glycoproteins"Humana Press, Totowa, NJ. 616 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 松井太衛: "別冊医学のあゆみ「血液疾患-state of arts」Ver.2(坂田,平井,溝口 編)von Willebrand因子の構造と生理機能(総説)"医歯薬出版,東京. 628 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 藤村吉博,千谷晃一: "Annual Review血液1999(高久,溝口,小宮山,坂田,金倉 編)V.血小板、4.von Willebrand病:病態生理と治療の新しい展開"中外医学社、東京. 257 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 松井太衛 他: "第7回血液アゴラヒト・フオンビルブラント因子に存在する血液型糖鎖の構造と意義"メディカルジャーナル社、東京. 12 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsui, T.et al.: "Interaction of von Willebrand Factor with the Extracellular Matrix and Glycocalicin under Static Conditions."J.Biochem.. 121. 376-381 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsui, T.et al.: "Kaouthiagin, a Matalloproteinase Purified from Naja kauthis Cobra Venom, Specifically Binds, to and Cleaves von Willebrand Factor (Abstract)."Blood. 90. 466a (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Miura, S.et al.: "Dimeric Structure of von Willebrand Factor A1-loop Region is Required to Show a Complete Inhibition on High-shear Stress Induced Platelet Aggregation (Abatract)."Blood. 90. 466a (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsui, T.et al.: "Complete Amino Acid Sequence of Bitiscetin, a Novel von Willebrand Factor Modulator Protein, Purified from Snake Venom of Bitis arietans."Res.Commun.Cell Mol.Biol.. 1. 271-284 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsui, T., and Titani, K.: "Chapter 19. ABO (H) Blood Group Expression on Circulating Glycoproteins."Methods in Molecular Medicine, Lectin Methods and Protocols, Vol.9 (Rhodes, J.M., and Milton, J.D., and Milton, J.D., eds.) Humana Press, Totowa, NJ. 235-245 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsui, T.et al.: "Purification and Amino Acid Sequence of Halystase from Snake Venom of Agkistrodon halys blomhoffi, a Serine Protease Specifically Cleaving Fibrinogen and Kininogen."Eur.J.Biochem.. 252. 569-575 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sakurai, Y.et al.: "The cDNA Cloning and Molecular Characterization of a Novel Snake Venom Platelet Glycoprotein Ib-binding Protein, Mamushigin."Thromb.Haemost.. 79. 1199-1207 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hamako, J.et al.: "Purification and Characterization of Kaouthiagin, a von Willebrand Factor-Binding and-Cleaving Metalloproteinase from Naja kauthia Cobra Venom."Thromb.Haemost.. 80. 499-505 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Makita, K.et al.: "Placental ecto-ATP Diphosphohydrolase : Its Structural Feature Distinct from CD39, Localization, and Inhibition on Shear-induced Platelet Aggregation."Int.J.Hematol.. 68. 297-310 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Miura, S.et al.: "Total Inhibition of High Shear Stress Induced Platelet Aggregation by Homodimeric von Willebrand Factor A1-loop Fragments."Br.J.Haematol.. 105. 1092-1100 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsui, T.et al.: "ABO Blood Group Antigens on Human Plasma von Willebrand Factor after ABO-Mismatched Bone Marrow Transplantation."Blood. 94. 2895-2900 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsumoto, M.et al: "The cDNA Cloning of Human Placental Ecto-ATP Diphophohydrolases I and II."FEBS Lett.. 453. 335-340 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsui, T.et al.: "Snake Venom Proteases Affecting Hemostasis and Thrombosis (Review)."Biochim.Biophys.Acta. 1477. 146-156 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yagi, H.et al.: "Plasmas with Upshaw-Schulman Syndrome, A Congenital Deficiency of von Willebrand Factor-cleaving Protease, Augment the Aggregation of Normal Washed Platelets under High-shear-stress (Abstract)."Blood. 96 (11-S-1). 630a (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsumoto, M.et al.: "Liver Transplantation Rescues a Deficient State of von Willebrand factor-cleaving Protease Activity in Patients with Liver Cirrhosis due to Congenital Biliary Atresia (Abstract)."Blood. 96 (11-S-1). 636a (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takatsuka, H.et al.: "Molecular Characterization of L-Amino Acid Oxidase from Agkistrodon halys blomhoffi with Special Reference to Platelet Aggregation."Biochim.Biophys.Acta. 1544. 207-277 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yagi, H.et al.: "Enhanced Low Shear Stress Induced Platelet Aggregation by Shiga-like Toxin 1 Purified from Escherichia coli 0157."Am.J.Hematol.. 66. 105-115 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsui, T.et al.: "Comparative Study of Blood Group-recognizing Lectins toward ABO Blood Group Antigens on Neoglycoproteins, Glycoproteins and Complex-type Oligosaccharides."Biochim.Biophys.Acta. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kinoshita, S.et al.: "Upshaw-Schulman Syndrome Revisited : A Concept of Congenital Thrombotic Thrombocytopenic Purpura."Int.J.Hematol.. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ito, M.et al.: "Complete Amino Acid Sequence of Kaouthiagin, a Novel Cobra Venom Metalloproteinase with Two Disintegrin-like Sequences."Biochemistry. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2002-03-26  

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