{"title":"因子 VIIa 中错综复杂的异构体:触发器。","authors":"Jesper J Madsen, Egon Persson, Ole H Olsen","doi":"10.1016/j.jtha.2024.08.026","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5000,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The intricate allostery in factor VIIa: triggering the trigger.\",\"authors\":\"Jesper J Madsen, Egon Persson, Ole H Olsen\",\"doi\":\"10.1016/j.jtha.2024.08.026\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":17326,\"journal\":{\"name\":\"Journal of Thrombosis and Haemostasis\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2024-09-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Thrombosis and Haemostasis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jtha.2024.08.026\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Thrombosis and Haemostasis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jtha.2024.08.026","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
The intricate allostery in factor VIIa: triggering the trigger.
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.
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.