- EMDB-26060: Cryo-em structure of human prothrombin:prothrombinase at 4.1 Angs... -
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基本情報
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データベース: EMDB / ID: EMD-26060
タイトル
Cryo-em structure of human prothrombin:prothrombinase at 4.1 Angstrom resolution
マップデータ
prothrombin:prothrombinase
試料
複合体: prothrombin prothrombinase
複合体: Prothrombin (E.C.3.4.21.5), Factor X light chain, Activated factor Xa heavy chain
タンパク質・ペプチド: Prothrombinトロンビン
タンパク質・ペプチド: Factor X light chain第X因子
タンパク質・ペプチド: Activated factor Xa heavy chain
複合体: Coagulation factor Va
タンパク質・ペプチド: Coagulation factor Va
タンパク質・ペプチド: Coagulation factor Va
機能・相同性
機能・相同性情報
response to vitamin K / 第X因子 / Α顆粒 / Cargo concentration in the ER / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / 循環器 / Extrinsic Pathway of Fibrin Clot Formation / COPII-mediated vesicle transport ...response to vitamin K / 第X因子 / Α顆粒 / Cargo concentration in the ER / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / 循環器 / Extrinsic Pathway of Fibrin Clot Formation / COPII-mediated vesicle transport / positive regulation of lipid kinase activity / COPII-coated ER to Golgi transport vesicle / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / トロンビン / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of astrocyte differentiation / positive regulation of TOR signaling / negative regulation of platelet activation / positive regulation of collagen biosynthetic process / negative regulation of cytokine production involved in inflammatory response / positive regulation of blood coagulation / negative regulation of fibrinolysis / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / regulation of cytosolic calcium ion concentration / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / endoplasmic reticulum-Golgi intermediate compartment membrane / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / platelet alpha granule lumen / Regulation of Complement cascade / acute-phase response / Cell surface interactions at the vascular wall / lipopolysaccharide binding / negative regulation of proteolysis / Post-translational protein phosphorylation / phospholipid binding / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / positive regulation of insulin secretion / 凝固・線溶系 / response to wounding / Golgi lumen / positive regulation of protein localization to nucleus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of reactive oxygen species metabolic process / extracellular vesicle / 凝固・線溶系 / antimicrobial humoral immune response mediated by antimicrobial peptide / Thrombin signalling through proteinase activated receptors (PARs) / Platelet degranulation / heparin binding / regulation of cell shape / positive regulation of cell growth / G alpha (q) signalling events / collagen-containing extracellular matrix / blood microparticle / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / positive regulation of protein phosphorylation / copper ion binding / G protein-coupled receptor signaling pathway / external side of plasma membrane / 小胞体 / signaling receptor binding / serine-type endopeptidase activity / calcium ion binding / positive regulation of cell population proliferation / タンパク質分解 / extracellular space / extracellular exosome / extracellular region / 生体膜 / 細胞膜 類似検索 - 分子機能
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
米国
引用
ジャーナル: Blood / 年: 2022 タイトル: Cryo-EM structure of the prothrombin-prothrombinase complex. 著者: Eliza A Ruben / Brock Summers / Michael J Rau / James A J Fitzpatrick / Enrico Di Cera / 要旨: The intrinsic and extrinsic pathways of the coagulation cascade converge to a common step where the prothrombinase complex, comprising the enzyme factor Xa (fXa), the cofactor fVa, Ca2+ and ...The intrinsic and extrinsic pathways of the coagulation cascade converge to a common step where the prothrombinase complex, comprising the enzyme factor Xa (fXa), the cofactor fVa, Ca2+ and phospholipids, activates the zymogen prothrombin to the protease thrombin. The reaction entails cleavage at 2 sites, R271 and R320, generating the intermediates prethrombin 2 and meizothrombin, respectively. The molecular basis of these interactions that are central to hemostasis remains elusive. We solved 2 cryogenic electron microscopy (cryo-EM) structures of the fVa-fXa complex, 1 free on nanodiscs at 5.3-Å resolution and the other bound to prothrombin at near atomic 4.1-Å resolution. In the prothrombin-fVa-fXa complex, the Gla domains of fXa and prothrombin align on a plane with the C1 and C2 domains of fVa for interaction with membranes. Prothrombin and fXa emerge from this plane in curved conformations that bring their protease domains in contact with each other against the A2 domain of fVa. The 672ESTVMATRKMHDRLEPEDEE691 segment of the A2 domain closes on the protease domain of fXa like a lid to fix orientation of the active site. The 696YDYQNRL702 segment binds to prothrombin and establishes the pathway of activation by sequestering R271 against D697 and directing R320 toward the active site of fXa. The cryo-EM structure provides a molecular view of prothrombin activation along the meizothrombin pathway and suggests a mechanism for cleavage at the alternative R271 site. The findings advance our basic knowledge of a key step of coagulation and bear broad relevance to other interactions in the blood.