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PreprintCited by 1Coagulation, Bradykinin, Polyphosphates, and AngioedemaBlood Coagulation and Thrombosis MechanismsHemophilia Treatment and Research

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Thrombin activation of the factor XI dimer is a multi-staged process for each subunit

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Barroeta, Awital Bar, Albanese, Pascal, Marquart, J. Arnoud, Meijers, Joost C.M., Scheltema, Richard A.·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.02.11.528103

Preprint — published as 10.1016/j.jtha.2023.12.038

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Abstract

Factor XI (FXI), a protein in the intrinsic coagulation pathway, can be activated by two enzymes. In hemostasis, FXI is activated by thrombin, while FXIIa-mediated activation is prothrombotic. The interactions between FXI and its activating enzymes are poorly understood due to their transient nature. Here, we applied structural proteomics, molecular dynamics simulations and binding assays to investigate the interface between thrombin and FXI including the dynamics underlying FXI activation. We demonstrate that activation of FXI is a multi-staged process, where thrombin first binds to Pro520 on FXI, after which it migrates towards the activation site by engaging the apple 1 domain and finally Arg378. We validated with known mutation sites and additionally found that Pro520 is conserved in prekallikrein (PK). This enables binding of thrombin even though it cannot activate PK. Understanding the exact binding of thrombin to FXI points a way for future interventions for bleeding or thrombosis.

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Metadata

Authors
Barroeta, A. B., Albanese, P., Marquart, J. A., Meijers, J. C. M., & Scheltema, R. A.
Affiliations
  • Sanquin (NL)
  • Utrecht University (NL)
Corresponding author
  • Meijers, Joost C.M.
  • Scheltema, Richard A.
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-02-11
DOI
10.1101/2023.02.11.528103
OpenAlex
W4320033448
Cited by
1
References
1
Citations by year
2023: 1
Type
posted content
Language
en
Open access
Licence
cc-by
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • European Commission (823839, HORIZON2020)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (741.018.201)
Topics
  • Health Sciences › Medicine › Hematology › Coagulation, Bradykinin, Polyphosphates, and Angioedema
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
Keywords
factor XI, thrombin, intrinsic coagulation pathway, thrombin binding site, prekallikrein, protein-protein interaction, coagulation activation, hemostasis, thrombosis

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