ArticleThe Journal of biological chemistry2020
Exosite binding drives substrate affinity for the activation of coagulation factor X by the intrinsic Xase complex.
Article in The Journal of biological chemistry, 2020. 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, 15 citations in OpenAlex.
- Structural basis for membrane binding by coagulation factors V and VIII and their specificity for phosphatidylserine-containing membranes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Protease domain exosites regulate extravascular binding of factor IX(a).Journal of thrombosis and haemostasis : JTH · 2025Article
- Factor IXa and factor X influence factor VIIIa stability and inactivation mechanisms in vitro and in vivo.Blood · 2025Article
- Protease engineering: Approaches, tools, and emerging trends.Biotechnology advances · 2025Review
- The Construction of a Molecular Model for the Ternary Protein Complex of Intrinsic Coagulation Pathway Factors Provides Novel Insights for the Pathogenesis of Cross-Reactive Material Positive Coagulation Factor Mutations.International journal of molecular sciences · 2025Article
- Nonallosteric activation of posttranslational modification enzymes by active site-directed inhibitors.Computational and structural biotechnology journal · 2024Article
- Review
- 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
- Article
- Probing activation-driven changes in coagulation factor IX by mass spectrometry.Journal of thrombosis and haemostasis : JTH · 2021Article
- Exosites expedite blood coagulation.The Journal of biological chemistry · 2020Article
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2 authors at 1 institution in 1 country.
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Abstract
Factor X activation by the intrinsic Xase complex, composed of factor IXa bound to factor VIIIa on membranes, is essential for the amplified blood coagulation response. The biological significance of this step is evident from bleeding arising from deficiencies in factors VIIIa or IXa in hemophilia. Here, we assess the mechanism(s) that enforce the distinctive specificity of intrinsic Xase for its biological substrate. Active-site function of IXa was assessed with a tripeptidyl substrate (PF-3688). The reversible S1 site binder, 4-aminobenzamidine (pAB), acted as a classical competitive inhibitor of PF-3688 cleavage by Xase. In contrast, pAB acted as a noncompetitive inhibitor of factor X activation. This disconnect between peptidyl substrate and protein substrate cleavage indicates a major role for interactions between factor X and extended sites on Xase in determining substrate affinity. Accordingly, an uncleavable factor X variant, not predicted to engage the active site of IXa within Xase, acted as a classical competitive inhibitor of factor X activation. Fluorescence studies confirmed the binding of factor X to Xase assembled with IXa with a covalently blocked active site. Our findings suggest that the recognition of factor X by the intrinsic Xase complex occurs through a multistep "dock-and-lock" pathway in which the initial interaction between factor X and intrinsic Xase occurs at exosites distant from the active site, followed by active-site docking and bond cleavage.
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