The intricate allostery in factor VIIa: triggering the trigger.

IF 5.5 2区 医学 Q1 HEMATOLOGY Journal of Thrombosis and Haemostasis Pub Date : 2024-09-26 DOI:10.1016/j.jtha.2024.08.026
Jesper J Madsen, Egon Persson, Ole H Olsen
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Abstract

In the last couple of decades, numerous investigations have shed considerable light on how precisely factor (F)VIIa mediates the initiation of blood coagulation upon association with its cofactor, tissue factor (TF). The role of the cofactor in this process is indispensable under physiological conditions, serving as a membrane-tethering allosteric activator of FVIIa also interacting with substrates (eg, FX). Available evidence reveals the induction and manifestation of complex allostery within FVIIa when stimulated by TF, involving at least 2 connected pathways spanning the interactive interface of the FVIIa-TF complex and the functional segments of FVIIa. Carefully designed FVIIa variants demonstrate corresponding modulations of their properties and response to TF-triggered allostery and activation. In addition, antibodies can stimulate FVIIa activity in both similar and distinctly different ways compared to that employed by TF. The mechanistic insights obtained through basic biochemical investigations have been validated through select engineered FVIIa constructs which, even in vivo, demonstrate beneficial, proof-of-concept effects. Altogether, we have recently gained unprecedented knowledge about and control over FVIIa allostery, enabling us to influence FVIIa activity in advanced manners and in a desired direction. Here, we summarize our current understanding of the allosteric activation of FVIIa ending up with some prospects of future investigations.

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因子 VIIa 中错综复杂的异构体:触发器。
在过去几十年中,大量研究揭示了因子 VIIa(FVIIa)与其辅助因子组织因子(TF)结合后如何精确介导血液凝固的启动过程。在生理条件下,辅助因子在这一过程中的作用是不可或缺的,它是 FVIIa 的膜系异位激活剂,还能与底物(如因子 X)相互作用。现有证据显示,在 TF 的刺激下,FVIIa 内的复杂异构体会被诱导并表现出来,这至少涉及两条相互连接的途径,横跨 FVIIa-TF 复合物的交互界面和 FVIIa 的功能片段。精心设计的 FVIIa 变体对其特性和对 TF 触发的异位和活化的反应有相应的调节作用。此外,与 TF 所采用的方式相比,抗体既能以相似的方式刺激 FVIIa 的活性,也能以截然不同的方式刺激 FVIIa 的活性。通过基础生化研究获得的机理认识已通过精选的工程 FVIIa 构建物得到验证,这些构建物甚至在体内也能显示出有益的概念验证效果。总之,我们最近对 FVIIa 异构体获得了前所未有的了解和控制,使我们能够以先进的方式和所需的方向影响 FVIIa 的活性。在此,我们总结了目前我们对 FVIIa 异构激活的理解,并展望了未来研究的一些前景。
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来源期刊
Journal of Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis 医学-外周血管病
CiteScore
24.30
自引率
3.80%
发文量
321
审稿时长
1 months
期刊介绍: The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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