The preAR2 region (1458–1492) in factor V-Short is crucial for the synergistic TFPIα-cofactor activity with protein S and the assembly of a trimolecular factor Xa-inhibitory complex comprising FV-Short, protein S, and TFPIα
(2022) In Journal of Thrombosis and Haemostasis 20(1). p.58-68- Abstract
Background: Factor V-Short (FV756-1458) is a natural splice variant in which 702 residues are deleted from the B domain. It exposes an acid region (AR2; 1493–1537) that binds tissue factor pathway inhibitor alpha (TFPIα). Protein S also interacts with TFPIα and serves as TFPIα-cofactor in factor Xa (FXa) inhibition. FV-Short and protein S function as synergistic TFPIα-cofactors in inhibition of FXa. FV810-1492 is an artificial FV-Short variant that cannot synergize with protein S as TFPIα cofactor even though it contains AR2 and binds TFPIα. Objective: To elucidate the mechanisms for the synergism between FV756-1458 and protein S as TFPIα cofactors. Methods: Four FV-Short variants were created, FV756-1458 and FV712-1458 contained the... (More)
Background: Factor V-Short (FV756-1458) is a natural splice variant in which 702 residues are deleted from the B domain. It exposes an acid region (AR2; 1493–1537) that binds tissue factor pathway inhibitor alpha (TFPIα). Protein S also interacts with TFPIα and serves as TFPIα-cofactor in factor Xa (FXa) inhibition. FV-Short and protein S function as synergistic TFPIα-cofactors in inhibition of FXa. FV810-1492 is an artificial FV-Short variant that cannot synergize with protein S as TFPIα cofactor even though it contains AR2 and binds TFPIα. Objective: To elucidate the mechanisms for the synergism between FV756-1458 and protein S as TFPIα cofactors. Methods: Four FV-Short variants were created, FV756-1458 and FV712-1458 contained the preAR2 region (1458–1492), whereas FV810-1492 and FV713-1492 lacked this region. The synergistic TFPIα cofactor activity between FV-Short variants and protein S was analyzed by FXa-inhibition. A microtiter-based assay tested binding between FV-Short variants, protein S, and TFPIα. Results: The two preAR2-containing FV-Short variants were active as synergistic TFPIα cofactors, whereas the other two were inactive. All variants bound to TFPIα. None of the FV-Short variants bound directly to protein S. The combination of TFPIα and preAR2-containing FV-Short variants bound protein S, whereas TFPIα together with the preAR2-minus variants did not. Protein S potentiated TFPIα-binding to the preAR2-containing variants and binding between TFPIα and protein S was stimulated only by the preAR2-containing variants. Conclusion: The preAR2 region is demonstrated to be crucial for the synergistic TFPIα-cofactor activity between FV-Short and protein S and for the assembly of a trimolecular FXa-inhibitory complex comprising FV-Short, protein S, and TFPIα.
(Less)
- author
- Dahlbäck, Björn LU and Tran, Sinh LU
- organization
- publishing date
- 2022-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Thrombosis and Haemostasis
- volume
- 20
- issue
- 1
- pages
- 11 pages
- publisher
- Wiley-Blackwell
- external identifiers
-
- scopus:85121703075
- pmid:34623729
- ISSN
- 1538-7933
- DOI
- 10.1111/jth.15547
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis
- id
- 7da5c7c4-5a59-4357-815f-2136189e5b43
- date added to LUP
- 2022-04-12 15:45:52
- date last changed
- 2024-04-21 20:13:47
@article{7da5c7c4-5a59-4357-815f-2136189e5b43,
abstract = {{<p>Background: Factor V-Short (FV756-1458) is a natural splice variant in which 702 residues are deleted from the B domain. It exposes an acid region (AR2; 1493–1537) that binds tissue factor pathway inhibitor alpha (TFPIα). Protein S also interacts with TFPIα and serves as TFPIα-cofactor in factor Xa (FXa) inhibition. FV-Short and protein S function as synergistic TFPIα-cofactors in inhibition of FXa. FV810-1492 is an artificial FV-Short variant that cannot synergize with protein S as TFPIα cofactor even though it contains AR2 and binds TFPIα. Objective: To elucidate the mechanisms for the synergism between FV756-1458 and protein S as TFPIα cofactors. Methods: Four FV-Short variants were created, FV756-1458 and FV712-1458 contained the preAR2 region (1458–1492), whereas FV810-1492 and FV713-1492 lacked this region. The synergistic TFPIα cofactor activity between FV-Short variants and protein S was analyzed by FXa-inhibition. A microtiter-based assay tested binding between FV-Short variants, protein S, and TFPIα. Results: The two preAR2-containing FV-Short variants were active as synergistic TFPIα cofactors, whereas the other two were inactive. All variants bound to TFPIα. None of the FV-Short variants bound directly to protein S. The combination of TFPIα and preAR2-containing FV-Short variants bound protein S, whereas TFPIα together with the preAR2-minus variants did not. Protein S potentiated TFPIα-binding to the preAR2-containing variants and binding between TFPIα and protein S was stimulated only by the preAR2-containing variants. Conclusion: The preAR2 region is demonstrated to be crucial for the synergistic TFPIα-cofactor activity between FV-Short and protein S and for the assembly of a trimolecular FXa-inhibitory complex comprising FV-Short, protein S, and TFPIα.</p>}},
author = {{Dahlbäck, Björn and Tran, Sinh}},
issn = {{1538-7933}},
language = {{eng}},
number = {{1}},
pages = {{58--68}},
publisher = {{Wiley-Blackwell}},
series = {{Journal of Thrombosis and Haemostasis}},
title = {{The preAR2 region (1458–1492) in factor V-Short is crucial for the synergistic TFPIα-cofactor activity with protein S and the assembly of a trimolecular factor Xa-inhibitory complex comprising FV-Short, protein S, and TFPIα}},
url = {{http://dx.doi.org/10.1111/jth.15547}},
doi = {{10.1111/jth.15547}},
volume = {{20}},
year = {{2022}},
}