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Structure paper

タイトル	Cryo-EM structure of coagulation factor Va bound to activated protein C.
ジャーナル・号・ページ	Blood, Vol. 145, Issue 26, Page 3166-3177, Year 2025
掲載日	2025年6月26日
著者	Bassem M Mohammed / Katherine Basore / Enrico Di Cera /
PubMed 要旨	Coagulation factor Va (FVa) is the cofactor component of the prothrombinase complex required for rapid generation of thrombin from prothrombin in the penultimate step of the coagulation cascade. In ...Coagulation factor Va (FVa) is the cofactor component of the prothrombinase complex required for rapid generation of thrombin from prothrombin in the penultimate step of the coagulation cascade. In addition, FVa is a target for proteolytic inactivation by activated protein C (APC). Like other protein-protein interactions in the coagulation cascade, the FVa-APC interaction has long posed a challenge to structural biology and its molecular underpinnings remain unknown. A recent cryogenic electron microscopy (cryo-EM) structure of FVa has revealed the arrangement of its A1-A2-A3-C1-C2 domains and the environment of the sites of APC cleavage at R306 and R506. Here, we report the cryo-EM structure of the FVa-APC complex at 3.15 Å resolution in which the protease domain of APC engages R506 in the A2 domain of FVa through electrostatic interactions between positively charged residues in the 30-loop and 70-loop of APC and an electronegative surface of FVa. The auxiliary γ-carboxyglutamic acid and epidermal growth factor domains of APC are highly dynamic and point to solvent, without making contacts with FVa. Binding of APC displaces a large portion of the A2 domain of FVa and projects the 654VKCIPDDDEDSYEIFEP670 segment as a "latch," or exosite ligand, over the 70-loop of the enzyme. The latch induces a large conformational change of the autolysis loop of APC, which in turn promotes docking of R506 into the primary specificity pocket. The cryo-EM structure of the FVa-APC complex validates the bulk of existing biochemical data and offers molecular context for a key regulatory interaction of the coagulation cascade.
リンク	Blood / PubMed:40324068
手法	EM (単粒子)
解像度	2.95 - 3.31 Å
構造データ	48439 9mov EMDB-48439, PDB-9mov: Cryo-EM structure of factor Va bound to activated protein C 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-48461: Cryo-EM structure of factor Va bound to activated protein C 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-48465: Cryo-EM structure of factor Va bound to activated protein C 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-48466: Cryo-EM structure of factor Va bound to activated protein C 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-48472: Cryo-EM structure of factor Va bound to activated protein C 手法: EM (単粒子) / 解像度: 2.95 Å EMDB-48473: Cryo-EM structure of factor Va bound to activated protein C 手法: EM (単粒子) / 解像度: 3.05 Å EMDB-48474: Cryo-EM structure of factor Va bound to activated protein C 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-48475: Cryo-EM structure of factor Va bound to activated protein C 手法: EM (単粒子) / 解像度: 3.31 Å 48481 9mot EMDB-48481, PDB-9mot: Cryo-EM structure of factor Va bound to activated protein C 手法: EM (単粒子) / 解像度: 3.15 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン ChemComp-CA: Unknown entry / カルシウムジカチオン
由来	homo sapiens (ヒト)
キーワード	BLOOD CLOTTING / Coagulation / Activated Factor V / Activated Protein C