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
Abstract
1. Introduction
2. Results
2.1. The Overall Structure of the Ternary Complex Model
2.2. The Critical Interaction Between Arg-562 of FVIIIa’s 558-Loop and the 333-Loop of FIXa Contributes to the Protection of FVIIIa from FXa Cleavage
2.3. The a2 Region of FVIIIa Drives the Opening of FIXa’s 266-Loop (c99-Loop) and Maintains Its Open State
2.4. FX Zymogen Contributes to Its Binding to FIXa and Facilitates the Activation of Itself in the Ternary Complex
2.5. FX Zymogen’s AP Stabilizes the Ternary Complex by Providing Double-Sided Interactions at the Interface of the Three Factors
2.6. A Detailed Proposal of the Assembly Process of FVIIIa-FIXa-FX (Zymogen) Complex
3. Discussion
4. Materials and Methods
4.1. Coagulation Factor Complex Construction with Alphafold2 and Alphafold-Multimer
4.2. Molecular Dynamics Simulation of Coagulation Factor Complexes
4.2.1. General
4.2.2. System Setup
4.2.3. System Equilibration
5. Summary
- Knot: A knot-like structure between Arg-562 of FVIIIa’s 558-Loop and the 333-Loop of FIXa contributes to FVIIIa-FIXa binding and the protection of FVIIIa from FXa cleavage, which might be the first reported case of protein–protein interactions;
- Lid: The a2 region of FVIIIa drives the opening of FIXa’s 266-Loop (c99-Loop) and maintains its open state, which may facilitate the binding of the substrate peptide from FX zymogen;
- Double-sided tape: The activation peptide (AP) of FX zymogen not only contributes to the binding of FX zymogen to FIXa and facilitates the activation of itself in the ternary complex but also stabilizes the ternary complex by providing double-sided interactions at the interface of the three factors.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Jiang, S.; Li, F.; Li, L.; Wang, X.; Wei, D.; Wu, W.; Xu, Q. 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. Int. J. Mol. Sci. 2025, 26, 5191. https://doi.org/10.3390/ijms26115191
Jiang S, Li F, Li L, Wang X, Wei D, Wu W, Xu Q. 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. 2025; 26(11):5191. https://doi.org/10.3390/ijms26115191
Chicago/Turabian StyleJiang, Shifeng, Fang Li, Lei Li, Xuefeng Wang, Dongqing Wei, Wenman Wu, and Qin Xu. 2025. "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 26, no. 11: 5191. https://doi.org/10.3390/ijms26115191
APA StyleJiang, S., Li, F., Li, L., Wang, X., Wei, D., Wu, W., & Xu, Q. (2025). 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, 26(11), 5191. https://doi.org/10.3390/ijms26115191