Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor X
Abstract: Formation of the extrinsic complex (EC) on cell surfaces is the event that triggers the coagulation cascade. Tissue factor (TF) and factor VIIa (FVIIa) form the EC together with FX on phosphatidylserine-containing membranes, leading to FX activation by TF:FVIIa. This lipid dependence has m...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952924007213 |
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| author | Melanie P. Muller Alex Mortenson Josepha C. Sedzro Po-Chao Wen James H. Morrissey Emad Tajkhorshid |
| author_facet | Melanie P. Muller Alex Mortenson Josepha C. Sedzro Po-Chao Wen James H. Morrissey Emad Tajkhorshid |
| author_sort | Melanie P. Muller |
| collection | DOAJ |
| description | Abstract: Formation of the extrinsic complex (EC) on cell surfaces is the event that triggers the coagulation cascade. Tissue factor (TF) and factor VIIa (FVIIa) form the EC together with FX on phosphatidylserine-containing membranes, leading to FX activation by TF:FVIIa. This lipid dependence has made experimental characterization of the EC structure challenging. Using a novel computational methodology combining rigid-body protein-protein docking and extensive nonequilibrium molecular dynamics simulations in the explicit presence of a membrane, we developed, to our knowledge, the first atomic-level model of the EC, taking full account of the role of the membrane. Rigid-body docking generated 1 000 000 protein-only structures that predict the binding of key EC domains. Residue-residue contact information was then used in nonequilibrium simulations to drive the formation of the EC on a phosphatidylserine/phosphatidylcholine membrane surface, providing, to our knowledge, the first membrane-bound model for the EC. Strikingly, in our model, FX makes contact with TF:FVIIa chiefly via its γ-carboxyglutamate–rich (GLA) domain and protease domain, with the majority of the FX light chain (ie, its 2 epidermal growth factor–like domains) out in the solvent, making no direct contact with TF:FVIIa. The TF exosite makes substantial contacts with both the FX- and FVIIa-GLA domains, in which TF residue K165 engages directly with the FVIIa-GLA domain, whereas K166 plays a central role in binding to the FX-GLA domain. These findings underscore the substrate-binding exosite of TF as being pivotal in the formation of the EC, serving as a critical interface linking the GLA domains of both FVIIa and FX. |
| format | Article |
| id | doaj-art-597d26927b5e4650b1edddbc9c4be97c |
| institution | Kabale University |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-597d26927b5e4650b1edddbc9c4be97c2025-02-12T05:31:38ZengElsevierBlood Advances2473-95292025-02-0194729740Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor XMelanie P. Muller0Alex Mortenson1Josepha C. Sedzro2Po-Chao Wen3James H. Morrissey4Emad Tajkhorshid5Theoretical and Computational Biophysics Group, National Institutes of Health Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, ILTheoretical and Computational Biophysics Group, National Institutes of Health Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, ILDepartment of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MITheoretical and Computational Biophysics Group, National Institutes of Health Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, ILDepartment of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI; James H. Morrissey, Department of Biological Chemistry, University of Michigan Medical School, 4301B MSRB III, 1150 West Medical Center Dr, Ann Arbor, MI 48109-5606;Theoretical and Computational Biophysics Group, National Institutes of Health Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, IL; Correspondence: Emad Tajkhorshid, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, 318 S Mathews Ave, Urbana, IL 61801;Abstract: Formation of the extrinsic complex (EC) on cell surfaces is the event that triggers the coagulation cascade. Tissue factor (TF) and factor VIIa (FVIIa) form the EC together with FX on phosphatidylserine-containing membranes, leading to FX activation by TF:FVIIa. This lipid dependence has made experimental characterization of the EC structure challenging. Using a novel computational methodology combining rigid-body protein-protein docking and extensive nonequilibrium molecular dynamics simulations in the explicit presence of a membrane, we developed, to our knowledge, the first atomic-level model of the EC, taking full account of the role of the membrane. Rigid-body docking generated 1 000 000 protein-only structures that predict the binding of key EC domains. Residue-residue contact information was then used in nonequilibrium simulations to drive the formation of the EC on a phosphatidylserine/phosphatidylcholine membrane surface, providing, to our knowledge, the first membrane-bound model for the EC. Strikingly, in our model, FX makes contact with TF:FVIIa chiefly via its γ-carboxyglutamate–rich (GLA) domain and protease domain, with the majority of the FX light chain (ie, its 2 epidermal growth factor–like domains) out in the solvent, making no direct contact with TF:FVIIa. The TF exosite makes substantial contacts with both the FX- and FVIIa-GLA domains, in which TF residue K165 engages directly with the FVIIa-GLA domain, whereas K166 plays a central role in binding to the FX-GLA domain. These findings underscore the substrate-binding exosite of TF as being pivotal in the formation of the EC, serving as a critical interface linking the GLA domains of both FVIIa and FX.http://www.sciencedirect.com/science/article/pii/S2473952924007213 |
| spellingShingle | Melanie P. Muller Alex Mortenson Josepha C. Sedzro Po-Chao Wen James H. Morrissey Emad Tajkhorshid Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor X Blood Advances |
| title | Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor X |
| title_full | Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor X |
| title_fullStr | Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor X |
| title_full_unstemmed | Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor X |
| title_short | Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor X |
| title_sort | membrane bound model of the ternary complex between factor viia tissue factor and factor x |
| url | http://www.sciencedirect.com/science/article/pii/S2473952924007213 |
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