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TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain

Reglinska-Matveyev, Natalia; Andersson, Helena M.; Rezende, Suely M.; Dahlbäck, Björn LU ; Crawley, James T. B.; Lane, David A. and Ahnstroem, Josefin (2014) In Blood 123(25). p.3979-3987
Abstract
Protein S is a cofactor for tissue factor pathway inhibitor (TFPI), accelerating the inhibition of activated factor X (FXa). TFPI Kunitz domain 3 residue Glu226 is essential for enhancement of TFPI by protein S. To investigate the complementary functional interaction site on protein S, we screened 44 protein S point, composite or domain swap variants spanning the whole protein S molecule for their TFPI cofactor function using a thrombin generation assay. Of these variants, two protein S/growth arrest-specific 6 chimeras, with either the whole sex hormone-binding globulin (SHBG)-like domain (Val243-Ser635; chimera III) or the SHBG laminin G-type 1 subunit (Ser283-Val459; chimera I), respectively, substituted by the corresponding domain in... (More)
Protein S is a cofactor for tissue factor pathway inhibitor (TFPI), accelerating the inhibition of activated factor X (FXa). TFPI Kunitz domain 3 residue Glu226 is essential for enhancement of TFPI by protein S. To investigate the complementary functional interaction site on protein S, we screened 44 protein S point, composite or domain swap variants spanning the whole protein S molecule for their TFPI cofactor function using a thrombin generation assay. Of these variants, two protein S/growth arrest-specific 6 chimeras, with either the whole sex hormone-binding globulin (SHBG)-like domain (Val243-Ser635; chimera III) or the SHBG laminin G-type 1 subunit (Ser283-Val459; chimera I), respectively, substituted by the corresponding domain in growth arrest-specific 6, were unable to enhance TFPI. The importance of the protein S SHBG-like domain (and its laminin G-type 1 subunit) for binding and enhancement of TFPI was confirmed in FXa inhibition assays and using surface plasmon resonance. In addition, protein S bound to C4b binding protein showed greatly reduced enhancement of TFPI-mediated inhibition of FXa compared with free protein S. We show that binding of TFPI to the protein S SHBG-like domain enables TFPI to interact optimally with FXa on a phospholipid membrane. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
123
issue
25
pages
3979 - 3987
publisher
American Society of Hematology
external identifiers
  • wos:000342617800022
  • scopus:84902668872
ISSN
1528-0020
DOI
10.1182/blood-2014-01-551812
language
English
LU publication?
yes
id
34e3fd64-e1ae-406c-af9d-8fee5b94db8f (old id 4803661)
date added to LUP
2014-12-01 07:37:52
date last changed
2017-06-25 03:08:28
@article{34e3fd64-e1ae-406c-af9d-8fee5b94db8f,
  abstract     = {Protein S is a cofactor for tissue factor pathway inhibitor (TFPI), accelerating the inhibition of activated factor X (FXa). TFPI Kunitz domain 3 residue Glu226 is essential for enhancement of TFPI by protein S. To investigate the complementary functional interaction site on protein S, we screened 44 protein S point, composite or domain swap variants spanning the whole protein S molecule for their TFPI cofactor function using a thrombin generation assay. Of these variants, two protein S/growth arrest-specific 6 chimeras, with either the whole sex hormone-binding globulin (SHBG)-like domain (Val243-Ser635; chimera III) or the SHBG laminin G-type 1 subunit (Ser283-Val459; chimera I), respectively, substituted by the corresponding domain in growth arrest-specific 6, were unable to enhance TFPI. The importance of the protein S SHBG-like domain (and its laminin G-type 1 subunit) for binding and enhancement of TFPI was confirmed in FXa inhibition assays and using surface plasmon resonance. In addition, protein S bound to C4b binding protein showed greatly reduced enhancement of TFPI-mediated inhibition of FXa compared with free protein S. We show that binding of TFPI to the protein S SHBG-like domain enables TFPI to interact optimally with FXa on a phospholipid membrane.},
  author       = {Reglinska-Matveyev, Natalia and Andersson, Helena M. and Rezende, Suely M. and Dahlbäck, Björn and Crawley, James T. B. and Lane, David A. and Ahnstroem, Josefin},
  issn         = {1528-0020},
  language     = {eng},
  number       = {25},
  pages        = {3979--3987},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain},
  url          = {http://dx.doi.org/10.1182/blood-2014-01-551812},
  volume       = {123},
  year         = {2014},
}