Molecular Mechanism of Extrinsic Blood Coagulation Pathway

外源性凝血途径的分子机制

基本信息

  • 批准号:
    03044113
  • 负责人:
  • 金额:
    $ 5.76万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for international Scientific Research
  • 财政年份:
    1991
  • 资助国家:
    日本
  • 起止时间:
    1991 至 1993
  • 项目状态:
    已结题

项目摘要

Initiation of the extrinsic blood coagulation pathway is mediated by a complex formed between plasma-derived factor VII/VIIa and cell-derived tissue factor (TF). To identify the site(s) of interaction, zymogen VII and VIIa were enzymatically and chemically modified, and their affinities with TF were estimated by measuring their inhibitory effects on the amidolytic activity enhanced after formation of the VIIa-TF complex. We found that the VIIa-light chain(Ki=3.5 X 10^<-7>) and its fragment consisting of the Gla-domain and the first epidermal growth factor (EGF)-like domain (Gla-EGF1 peptide ; Ki=1.0 X 10^<-6>) have an affinity with TF, but their binding capacity disappeared, respectively, by conventional chymotryptic cleavage.Therefore, one of the binding sites of VII with TF probably locates in the Gla-EGF1 region. On the other hand, a dansyl-Glu-Gly-Arg chloromethyl ketone-treated Gla-domainless VIIa(Ki=0.7 X 10^<-7>) showed a high affinity with TF, whereas the corresponding Gla-doma … More inless VII similarly treated showed no binding potential, thereby indicating that binding site(s) other than in the Gla-EGF1 region is present in VIIa but not in VII. Acetylation or carbamylation of alpha-amino group of NH_2-terminal Ile-153 of VIIa resulted in the loss of binding affinity with TF ; such modifications convert VIIa into a zymogen like inactive form by destroying the salt bridge between Ile-153 and Asp343 in VIIa. The carbamylation rate of VIIa in the presence of TF was low, as compared with that in the absence of TF. The protection of alpha-amino group of Ile-153 from carbamylation after complex formation seemed to be due to a salt bridge formation between Ile-153 and Asp-343 in VIIa-TF complex. Therefore, it is concluded that the binding of TF with the heavy chain of VIIa induces a specific conformational change that brings alpha-amino group of Ile-153 close to beta-carboxyl group of Asp-343 to make a stable salt bridge. This salt bridge formed only in the presence of TF is essential for the formation of the catalytic triad of VIIa. Less
外源性凝血途径的启动是由血浆衍生因子VII/VIIa和细胞衍生组织因子(Tf)形成的复合体介导的。为了确定相互作用的位点(S),对VIIa和VIIa进行了酶修饰和化学修饰,并通过测定它们对VIIa-Tf络合物形成后增强的氨解活性的抑制作用来评估它们与Tf的亲和力。我们发现,VIIa轻链(Ki=3.5×10^&lt;-7&gt;)及其由GLA-结构域和第一表皮生长因子(EGF)样结构域组成的片段(GLA-EGF1多肽;Ki=1.0 X 10^&lt;-6&gt;)与Tf具有亲和力,但它们的结合能力分别被常规的乳凝乳酶切割所消除,因此,VII与Tf的结合位点之一可能位于GLA-EGF1区域。另一方面,丹氨酰-谷氨酸-甘氨酸-精氨酸氯甲基酮处理的无GLA结构域的VIIa(Ki=0.7X10;-7)与Tf有很高的亲和力,而相应的Gla-DOMA…VIIa的NH_2-末端Ile-153的α-氨基的乙酰化或氨基甲基化导致与Tf的结合失去亲和力,这种修饰通过破坏VIIa中Ile-153和Asp343之间的盐桥而将VIIa转变为类酶原的非活性形式。有Tf存在时,VIIa的氨甲酰化速率比无Tf时低。Ile-153的α-氨基的保护作用可能是由于在VIIa-Tf复合体中Ile-153与Asp-343之间形成盐桥所致。因此,Tf与VIIa重链的结合引起了特异的构象变化,使Ile-153的α-氨基接近Asp-343的β-羧基,形成稳定的盐桥。这种只在Tf存在下形成的盐桥对于VIIa催化三联体的形成是必不可少的。较少

项目成果

期刊论文数量(57)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
西村 仁: "糖鎖の多様な世界" 講談社サイエンティフィック, 16 (1993)
西村仁:“糖链的多样化世界”讲谈社科学,16(1993)
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    0
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Nishimura,H.,Yamashita,S.,Zeng,Z.,Walz,D.A.,and Iwanaga,S.: "Evidence for the Existence of O-linked Sugar Chains Consisting of Glucose and Xylose in Bovine Thrombospondin." J.Biochem.111. 460-464 (1992)
Nishimura,H.、Yamashita,S.、Zeng,Z.、Walz,D.A. 和 Iwanaga,S.:“牛血小板反应蛋白中存在由葡萄糖和木糖组成的 O-连接糖链的证据”。
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    0
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Tokunaga,F.,et al.: "Purification and Characterization of Lipoplysaccharide-sensitive Serine Protease Zymogen (factor C) Isolated from Limulus polyphemus Hemocytes:A Newly Identified Intracellular Zymogen Activated by α-Chymotrypsin,not by Trypsin." J.Bio
Tokunaga, F., 等人:“从鲎血细胞中分离出的脂多糖敏感丝氨酸蛋白酶酶原(C 因子)的纯化和表征:一种新鉴定的由 α-胰凝乳蛋白酶而非胰蛋白酶激活的细胞内酶原,J.Bio。”
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  • 影响因子:
    0
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  • 通讯作者:
Morita,T.,et al.: "γ-Carboxyglutamic Acid (Gla)-Domainless Blood Coagulation Factor IXa Species:Preparation and Properties." J.Biochem.110. 990-996 (1991)
Morita, T., et al.:“γ-羧基谷氨酸 (Gla)-无域凝血因子 IXa 物种:制备和特性。J.Biochem.110 (1991)。
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    0
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Shun-ichiro Kawabata: "Rabbit Liver Microsomal Endopeptidase with Substrate Specifity for processing proproteins is Structurally Related to Rat Testes Metalloendopeptidase 24.15." J.Biol.Chem.268(17). 12498-12503 (1993)
Shun-ichiro Kawabata:“具有处理前蛋白底物特异性的兔肝微粒体内肽酶在结构上与大鼠睾丸金属内肽酶 24.15 相关。”
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IWANAGA Sadaaki其他文献

IWANAGA Sadaaki的其他文献

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{{ truncateString('IWANAGA Sadaaki', 18)}}的其他基金

Role of Limulus Hemocytes in the Biological Defense System.
鲎血细胞在生物防御系统中的作用。
  • 批准号:
    04404090
  • 财政年份:
    1992
  • 资助金额:
    $ 5.76万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (A)
Basic studies on Development of Anti-thrombotic Agents
抗血栓药物开发的基础研究
  • 批准号:
    04557015
  • 财政年份:
    1992
  • 资助金额:
    $ 5.76万
  • 项目类别:
    Grant-in-Aid for Developmental Scientific Research (B)
Studies on the Activity Measurement for Blood Proteases using their Monoclonal Antibodies
用单克隆抗体测定血液蛋白酶活性的研究
  • 批准号:
    02557016
  • 财政年份:
    1990
  • 资助金额:
    $ 5.76万
  • 项目类别:
    Grant-in-Aid for Developmental Scientific Research (B)
Mechanism of Hemolymph Coagulation System in Invertebrates
无脊椎动物血淋巴凝固系统的机制
  • 批准号:
    02454539
  • 财政年份:
    1990
  • 资助金额:
    $ 5.76万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
Initiation Mechanism of Extrinsic Blood Coagulation System
外源性凝血系统的启动机制
  • 批准号:
    63044110
  • 财政年份:
    1988
  • 资助金额:
    $ 5.76万
  • 项目类别:
    Grant-in-Aid for international Scientific Research
Development of Synthetic Fluorogenic Peptide Substrates for Blood Clotting Proteases
凝血蛋白酶合成荧光肽底物的开发
  • 批准号:
    63870017
  • 财政年份:
    1988
  • 资助金额:
    $ 5.76万
  • 项目类别:
    Grant-in-Aid for Developmental Scientific Research
Hemolymph Coagulation and Defence Systems in Invertebrate Animals
无脊椎动物的血淋巴凝固和防御系统
  • 批准号:
    62480453
  • 财政年份:
    1987
  • 资助金额:
    $ 5.76万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
Development and Application of Fluorogenic Peptide Substrates for Determination fo Blood Clotting Proteases
凝血蛋白酶测定荧光肽底物的研制及应用
  • 批准号:
    61880016
  • 财政年份:
    1986
  • 资助金额:
    $ 5.76万
  • 项目类别:
    Grant-in-Aid for Developmental Scientific Research
Studies on Molecular Abnormality of Blood Coagulation and Fibrinolytic Factors
凝血及纤溶因子分子异常研究
  • 批准号:
    60480497
  • 财政年份:
    1985
  • 资助金额:
    $ 5.76万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)

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病原体诱导的血液凝固中脂质过氧化和焦亡诱导的组织因子激活
  • 批准号:
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HIV pathology and infection mediated by host-derived tissue factor on the virus: A broad-spectrum antiviral target.
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    2022
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Tissue factor-dependent coagulation in thrombosis and immune responses
血栓形成和免疫反应中的组织因子依赖性凝血
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    2021
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Excellence in Research: Molecular mechanism of Tissue Factor encryption and decryption.
卓越研究:组织因子加密和解密的分子机制。
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    2100878
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    2021
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宿主细胞源性组织因子作为病毒病理学和感染的广谱基础
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胶质母细胞瘤中受体酪氨酸激酶的组织因子调节
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组织因子、连接粘附分子 A 和整合素 B1 之间的相互作用驱动胶质母细胞瘤的自我更新
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    10331881
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Interaction between Tissue Factor, Junctional Adhesion Molecule-A, and Integrin B1 to drive self-renewal in glioblastoma
组织因子、连接粘附分子 A 和整合素 B1 之间的相互作用驱动胶质母细胞瘤的自我更新
  • 批准号:
    10554404
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    2020
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