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The LIKT sequence in C-terminus of tissue factor pathway inhibitor (TFPIα) crucially important for the synergistic TFPIα-cofactor activity of protein S and FV-short Authors

Dahlbäck, Björn LU ; Tran, Sinh LU and Draczkowski, Piotr (2026) In Bleeding, Thrombosis and Vascular Biology 5(3).
Abstract
Background: Inhibition of factor Xa (FXa) by tissue factor pathway inhibitor α (TFPIα) is potentiated by FV-Short and protein S. The C-terminus of TFPIα is important for formation of the TFPIα/protein S/FV-Short complex. It contains a hydrophobic sequence (LIKT). The purpose was to investigate the importance of the LIKT sequence.

Methods: Two TFPIα C-terminal peptides were synthesized, one wild-type and the other with LIKT replaced by AAKA. The effect of the peptides on TFPIα function was tested. An AAKA-mutant TFPIα was created and compared with wild-type TFPIα. AlphaFold was used to elucidate a mechanism for the role of the LIKT sequence.

Results: The wild-type peptide efficiently inhibited the FXa-inhibitory activity... (More)
Background: Inhibition of factor Xa (FXa) by tissue factor pathway inhibitor α (TFPIα) is potentiated by FV-Short and protein S. The C-terminus of TFPIα is important for formation of the TFPIα/protein S/FV-Short complex. It contains a hydrophobic sequence (LIKT). The purpose was to investigate the importance of the LIKT sequence.

Methods: Two TFPIα C-terminal peptides were synthesized, one wild-type and the other with LIKT replaced by AAKA. The effect of the peptides on TFPIα function was tested. An AAKA-mutant TFPIα was created and compared with wild-type TFPIα. AlphaFold was used to elucidate a mechanism for the role of the LIKT sequence.

Results: The wild-type peptide efficiently inhibited the FXa-inhibitory activity of TFPIα/protein S/FV-Short complex, whereas the AAKA peptide did not. The LIKT sequence in TFPIα was crucially important for the synergistic TFPIα-cofactor activity between protein S and FV-Short. AlphaFold (DeepMind, London, UK) suggested an interaction between LIKT and FV-Short B-loop 1510-1517 mediated through a network of hydrogen bonds and hydrophobic interactions.

Conclusions: The C-terminal TFPIα-peptide induced complex formation between protein S and FV-Short. The LIKT sequence in TFPIα was crucially important for the ability of protein S and FV-Short to function as synergistic TFPIα cofactors. (Less)
Abstract (Swedish)
Background: Inhibition of factor Xa (FXa) by tissue factor pathway inhibitor α (TFPIα) is potentiated by FV-Short and protein S. The C-terminus of TFPIα is important for formation of the TFPIα/protein S/FV-Short complex. It contains a hydrophobic sequence (LIKT). The purpose was to investigate the importance of the LIKT sequence.
Methods: Two TFPIα C-terminal peptides were synthesized, one wild-type and the other with LIKT replaced by AAKA. The effect of the peptides on TFPIα function was tested. An AAKA-mutant TFPIα was created and compared with wild-type TFPIα. AlphaFold was used to elucidate a mechanism for the role of the LIKT sequence.
Results: The wild-type peptide efficiently inhibited the FXa-inhibitory activity of... (More)
Background: Inhibition of factor Xa (FXa) by tissue factor pathway inhibitor α (TFPIα) is potentiated by FV-Short and protein S. The C-terminus of TFPIα is important for formation of the TFPIα/protein S/FV-Short complex. It contains a hydrophobic sequence (LIKT). The purpose was to investigate the importance of the LIKT sequence.
Methods: Two TFPIα C-terminal peptides were synthesized, one wild-type and the other with LIKT replaced by AAKA. The effect of the peptides on TFPIα function was tested. An AAKA-mutant TFPIα was created and compared with wild-type TFPIα. AlphaFold was used to elucidate a mechanism for the role of the LIKT sequence.
Results: The wild-type peptide efficiently inhibited the FXa-inhibitory activity of TFPIα/protein S/FV-Short complex, whereas the AAKA peptide did not. The LIKT sequence in TFPIα was crucially important for the synergistic TFPIα-cofactor activity between protein S and FV-Short. AlphaFold (DeepMind, London, UK) suggested an interaction between LIKT and FV-Short B-loop 1510-1517 mediated through a network of hydrogen bonds and hydrophobic interactions.
Conclusions: The C-terminal TFPIα-peptide induced complex formation between protein S and FV-Short. The LIKT sequence in TFPIα was crucially important for the ability of protein S and FV-Short to function as synergistic TFPIα cofactors. (Less)
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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Bleeding, Thrombosis and Vascular Biology
volume
5
issue
3
article number
414
ISSN
2785-5309
DOI
10.4081/btvb.2026.414
language
English
LU publication?
yes
id
c778e4c7-d1b8-4571-bbed-8ed06464b3f8
date added to LUP
2026-09-10 00:30:52
date last changed
2026-09-10 08:22:44
@article{c778e4c7-d1b8-4571-bbed-8ed06464b3f8,
  abstract     = {{Background: Inhibition of factor Xa (FXa) by tissue factor pathway inhibitor α (TFPIα) is potentiated by FV-Short and protein S. The C-terminus of TFPIα is important for formation of the TFPIα/protein S/FV-Short complex. It contains a hydrophobic sequence (LIKT). The purpose was to investigate the importance of the LIKT sequence.<br/><br/>Methods: Two TFPIα C-terminal peptides were synthesized, one wild-type and the other with LIKT replaced by AAKA. The effect of the peptides on TFPIα function was tested. An AAKA-mutant TFPIα was created and compared with wild-type TFPIα. AlphaFold was used to elucidate a mechanism for the role of the LIKT sequence.<br/><br/>Results: The wild-type peptide efficiently inhibited the FXa-inhibitory activity of TFPIα/protein S/FV-Short complex, whereas the AAKA peptide did not. The LIKT sequence in TFPIα was crucially important for the synergistic TFPIα-cofactor activity between protein S and FV-Short. AlphaFold (DeepMind, London, UK) suggested an interaction between LIKT and FV-Short B-loop 1510-1517 mediated through a network of hydrogen bonds and hydrophobic interactions.<br/><br/>Conclusions: The C-terminal TFPIα-peptide induced complex formation between protein S and FV-Short. The LIKT sequence in TFPIα was crucially important for the ability of protein S and FV-Short to function as synergistic TFPIα cofactors.}},
  author       = {{Dahlbäck, Björn and Tran, Sinh and Draczkowski, Piotr}},
  issn         = {{2785-5309}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{3}},
  series       = {{Bleeding, Thrombosis and Vascular Biology}},
  title        = {{The LIKT sequence in C-terminus of tissue factor pathway inhibitor (TFPIα) crucially important for the synergistic TFPIα-cofactor activity of protein S and FV-short Authors}},
  url          = {{http://dx.doi.org/10.4081/btvb.2026.414}},
  doi          = {{10.4081/btvb.2026.414}},
  volume       = {{5}},
  year         = {{2026}},
}