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Thrombin activation of the factor XI dimer is a multistaged process for each subunit.
Bar Barroeta, Awital; Albanese, Pascal; Kadavá, Tereza; Jankevics, Andris; Marquart, J Arnoud; Meijers, Joost C M; Scheltema, Richard A.
Afiliación
  • Bar Barroeta A; Department of Molecular Hematology, Sanquin, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, the Netherlands.
  • Albanese P; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Netherlands Proteomics Centre, Utrecht, The Netherlands.
  • Kadavá T; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Netherlands Proteomics Centre, Utrecht, The Netherlands.
  • Jankevics A; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Netherlands Proteomics Centre, Utrecht, The Netherlands; Univ. Grenoble Alpes, CNRS, INRAE, CEA, LPCV, INSERM, UMR
  • Marquart JA; Department of Molecular Hematology, Sanquin, Amsterdam, the Netherlands.
  • Meijers JCM; Department of Molecular Hematology, Sanquin, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, the Netherlands; Department of Experimental Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic
  • Scheltema RA; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Netherlands Proteomics Centre, Utrecht, The Netherlands; Department of Biochemistry, Cell & Systems Biology, In
J Thromb Haemost ; 22(5): 1336-1346, 2024 May.
Article en En | MEDLINE | ID: mdl-38242207
ABSTRACT

BACKGROUND:

Factor (F)XI can be activated by proteases, including thrombin and FXIIa. The interactions of these enzymes with FXI are transient in nature and therefore difficult to study.

OBJECTIVES:

To identify the binding interface between thrombin and FXI and understand the dynamics underlying FXI activation.

METHODS:

Crosslinking mass spectrometry was used to localize the binding interface of thrombin on FXI. Molecular dynamics simulations were applied to investigate conformational changes enabling thrombin-mediated FXI activation after binding. The proposed trajectory of activation was examined with nanobody 1C10, which was previously shown to inhibit thrombin-mediated activation of FXI.

RESULTS:

We identified a binding interface of thrombin located on the light chain of FXI involving residue Pro520. After this initial interaction, FXI undergoes conformational changes driven by binding of thrombin to the apple 1 domain in a secondary step to allow migration toward the FXI cleavage site. The 1C10 binding site on the apple 1 domain supports this proposed trajectory of thrombin. We validated the results with known mutation sites on FXI. As Pro520 is conserved in prekallikrein (PK), we hypothesized and showed that thrombin can bind PK, even though it cannot activate PK.

CONCLUSION:

Our investigations show that the activation of FXI is a multistaged procedure. Thrombin first binds to Pro520 in FXI; thereafter, it migrates toward the activation site by engaging the apple 1 domain. This detailed analysis of the interaction between thrombin and FXI paves a way for future interventions for bleeding or thrombosis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Unión Proteica / Factor XI / Trombina / Simulación de Dinámica Molecular Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Unión Proteica / Factor XI / Trombina / Simulación de Dinámica Molecular Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido