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抗凝蛋白 C 激活的蛋白酶对因子 V 的调节:B 结构域和 TFPIα 的影响。

Regulation of factor V by the anticoagulant protease activated protein C: Influence of the B-domain and TFPIα.

机构信息

Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

出版信息

J Biol Chem. 2022 Nov;298(11):102558. doi: 10.1016/j.jbc.2022.102558. Epub 2022 Sep 30.

Abstract

Activated protein C (APC) is an important anticoagulant protein that regulates thrombin generation through inactivation of factor V (FV) and activated factor V (FVa). The rate of APC inactivation of FV is slower compared to FVa, although proteolysis occurs at the same sites (Arg, Arg, and Arg). The molecular basis for FV resistance to APC is unknown. Further, there is no information about how FV-short, a physiologically relevant isoform of FV with a shortened B-domain, is regulated by APC. Here, we identify the molecular determinants which differentially regulate APC recognition of FV versus FVa and uncover how FV-short can be protected from this anticoagulant pathway. Using recombinant FV derivatives and B-domain fragments, we show that the conserved basic region (BR; 963-1008) within the central portion of the B-domain plays a major role in limiting APC cleavage at Arg. Derivatives of FV lacking the BR, including FV-short, were subject to rapid cleavage at Arg and were inactivated like FVa. The addition of a FV-BR fragment reversed this effect and delayed APC inactivation. We also found that anticoagulant glycoprotein TFPIα, which has a C-terminal BR homologous to FV-BR, protects FV-short from APC inactivation by delaying cleavage at Arg. We conclude that the FV-BR plays a major role in protecting FV from APC inactivation. Using a similar mechanistic strategy, TFPIα also shields FV-short from APC. These findings clarify the resistance of FV to APC, advance our understanding of FV/FVa regulation, and establish a mechanistic framework for manipulating this reaction to alter coagulation.

摘要

活化蛋白 C (APC) 是一种重要的抗凝蛋白,通过灭活因子 V (FV) 和活化因子 V (FVa) 来调节凝血酶生成。APC 对 FV 的灭活速度比 FVa 慢,尽管在相同的部位 (Arg、Arg 和 Arg) 发生蛋白水解。FV 对 APC 产生抗性的分子基础尚不清楚。此外,关于生理相关的 FV 短异构体 (FV-short) 如何受 APC 调节,目前尚无信息。在这里,我们确定了差异调节 APC 识别 FV 与 FVa 的分子决定因素,并揭示了 FV-short 如何免受这种抗凝途径的影响。我们使用重组 FV 衍生物和 B 结构域片段,表明 B 结构域中部的保守碱性区域 (BR; 963-1008) 在限制 APC 在 Arg 处切割方面起着主要作用。缺乏 BR 的 FV 衍生物,包括 FV-short,在 Arg 处易受快速切割,并像 FVa 一样失活。添加 FV-BR 片段可逆转这种效应并延迟 APC 失活。我们还发现,具有与 FV-BR 同源的 C 末端 BR 的抗凝糖蛋白 TFPIα 通过延迟 Arg 处的切割来保护 FV-short 免受 APC 失活。我们得出结论,FV-BR 在保护 FV 免受 APC 失活方面起着主要作用。使用类似的机制策略,TFPIα 还可保护 FV-short 免受 APC 的失活。这些发现阐明了 FV 对 APC 的抗性,增进了我们对 FV/FVa 调节的理解,并建立了一种用于操纵该反应以改变凝血的机制框架。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b25b/9637641/3941085c982d/gr1.jpg

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