ArticleThe Journal of biological chemistry2016
Molecular Basis of Enhanced Activity in Factor VIIa-Trypsin Variants Conveys Insights into Tissue Factor-mediated Allosteric Regulation of Factor VIIa Activity.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 23 citations in OpenAlex.
- Overview of Venous Thromboembolism and Emerging Therapeutic Technologies Based on Nanocarriers-Mediated Drug Delivery Systems.Molecules (Basel, Switzerland) · 2024Review
- An RNA aptamer exploits exosite-dependent allostery to achieve specific inhibition of coagulation factor IXa.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Elucidating the complex membrane binding of a protein with multiple anchoring domains using extHMMM.PLoS computational biology · 2024Article
- A systematic approach for evaluating the role of surface-exposed loops in trypsin-like serine proteases applied to the 170 loop in coagulation factor VIIa.Scientific reports · 2022Article
- Uncovering Membrane-Bound Models of Coagulation Factors by Combined Experimental and Computational Approaches.Thrombosis and haemostasis · 2021Review
- Article
- Beating tissue factor at its own game: Design and properties of a soluble tissue factor-independent coagulation factor VIIa.The Journal of biological chemistry · 2020Article
- Allostery in Coagulation Factor VIIa Revealed by Ensemble Refinement of Crystallographic Structures.Biophysical journal · 2019Article
- Orphan Three-Finger Toxins Bind at Tissue Factor-Factor VIIa Interface to Inhibit Factor X Activation: Identification of Functional Site by Docking.TH open : companion journal to thrombosis and haemostasis · 2018Article
- Evolutionary conservation of the allosteric activation of factor VIIa by tissue factor in lamprey.Journal of thrombosis and haemostasis : JTH · 2018Article
- Engineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors.Nature communications · 2017Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The complex of coagulation factor VIIa (FVIIa), a trypsin-like serine protease, and membrane-bound tissue factor (TF) initiates blood coagulation upon vascular injury. Binding of TF to FVIIa promotes allosteric conformational changes in the FVIIa protease domain and improves its catalytic properties. Extensive studies have revealed two putative pathways for this allosteric communication. Here we provide further details of this allosteric communication by investigating FVIIa loop swap variants containing the 170 loop of trypsin that display TF-independent enhanced activity. Using x-ray crystallography, we show that the introduced 170 loop from trypsin directly interacts with the FVIIa active site, stabilizing segment 215-217 and activation loop 3, leading to enhanced activity. Molecular dynamics simulations and novel fluorescence quenching studies support that segment 215-217 conformation is pivotal to the enhanced activity of the FVIIa variants. We speculate that the allosteric regulation of FVIIa activity by TF binding follows a similar path in conjunction with protease domain N terminus insertion, suggesting a more complete molecular basis of TF-mediated allosteric enhancement of FVIIa activity.
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