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

Summary, in English

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: Natalia Reglinska-Matveyev; Helena M. Andersson; Suely M. Rezende; Björn Dahlbäck; James T. B. Crawley; David A. Lane; Josefin Ahnstroem
• Department/s: Clinical Chemistry, Malmö
• Publishing year: 2014
• Language: English
• Pages: 3979-3987
• Publication/Series: Blood
• Volume: 123
• Issue: 25
• Links: http://dx.doi.org/10.1182/blood-2014-01-551812
• Document type: Journal article
• Publisher: American Society of Hematology
• Topic: Hematology
• Status: Published
• Research group: Clinical Chemistry, Malmö
• ISBN/ISSN/Other: ISSN: 1528-0020