Imperial College London
Portrait Picture

Emeritus Professor David Lane

Faculty of Medicine, Department of Immunology and Inflammation

Emeritus Professor of Haematology
 
 
 
//

Contact

 

+44 (0)20 3313 2295d.lane

 
 
//

Location

 

Commonwealth BuildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Teraz-Orosz:2022:10.1182/bloodadvances.2021005382,
author = {Teraz-Orosz, A and Gierula, M and Petri, A and Jones, DA and Keniyopoullos, R and Badia, Folgado P and Santamaria, S and Crawley, JTB and Lane, DA and Ahnstrom, J},
doi = {10.1182/bloodadvances.2021005382},
journal = {Blood Advances},
pages = {704--715},
title = {Laminin G1 residues of protein S mediate its TFPI cofactor function and are competitively regulated by C4BP.},
url = {http://dx.doi.org/10.1182/bloodadvances.2021005382},
volume = {6},
year = {2022}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Protein S is a cofactor in the tissue factor pathway inhibitor (TFPI) anticoagulant pathway. It enhances TFPIα-mediated inhibition of factor (F)Xa activity and generation. The enhancement is dependent on a TFPIα-protein S interaction, involving TFPIα Kunitz 3 and protein S laminin G-type (LG)-1. C4b binding protein (C4BP), which binds to protein S LG1, almost completely abolishes its TFPI cofactor function. However, neither the amino acids involved in TFPIα enhancement, nor the mechanisms underlying the reduced TFPI cofactor function of C4BP-bound protein S, are known. To screen for functionally important regions within protein S LG1 we generated seven variants with inserted N-linked glycosylation attachment sites. Protein S D253T and Q427N/K429T, displayed severely reduced TFPI cofactor function while showing normal activated protein C (APC) cofactor function and C4BP binding. Based on these results, we designed four protein S variants in which 4-6 surface exposed charged residues were substituted for alanine. One variant, protein S K255A/E257A/D287A/R410A/K423A/E424A, exhibited either abolished or severely reduced TFPI cofactor function in plasma and FXa inhibition assays, both in the presence or absence of FV-short, but retained normal APC cofactor function and high affinity C4BP-binding. The C4BP β-chain was expressed to determine the mechanisms behind the reduced TFPI cofactor function of C4BP-bound protein S. Like C4BP-bound protein S, C4BP β-chain-bound protein S had severely reduced TFPI cofactor function. These results show that protein S Lys255, Glu257, Asp287, Arg410, Lys423 and Glu424 are critical for protein S-mediated enhancement of TFPIα and that binding of the C4BP β-chain blocks this function.
AU  - Teraz-Orosz,A
AU  - Gierula,M
AU  - Petri,A
AU  - Jones,DA
AU  - Keniyopoullos,R
AU  - Badia,Folgado P
AU  - Santamaria,S
AU  - Crawley,JTB
AU  - Lane,DA
AU  - Ahnstrom,J
DO  - 10.1182/bloodadvances.2021005382
EP  - 715
PY  - 2022///
SN  - 2473-9529
SP  - 704
TI  - Laminin G1 residues of protein S mediate its TFPI cofactor function and are competitively regulated by C4BP.
T2  - Blood Advances
UR  - http://dx.doi.org/10.1182/bloodadvances.2021005382
UR  - https://www.ncbi.nlm.nih.gov/pubmed/34731882
UR  - https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2021005382/477773/Laminin-G1-residues-of-protein-S-mediate-its-TFPI
UR  - http://hdl.handle.net/10044/1/92858
VL  - 6
ER  -
Download