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The preAR2 region (...
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
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- Dahlbäck, Björn (författare)
- Lund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups
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- Tran, Sinh (författare)
- Lund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups
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(creator_code:org_t)
- Elsevier BV, 2022
- 2022
- Engelska 11 s.
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 20:1, s. 58-68
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Abstract
Ämnesord
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- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
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