Imperial College London
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DrSalvatoreSantamaria

Faculty of Medicine, Department of Immunology and Inflammation

Honorary Lecturer
 
 
 
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Contact

 

s.santamaria

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Gierula:2019:10.1111/jth.14594,
author = {Gierula, M and SallesCrawley, II and Santamaria, S and TerazOrosz, A and Crawley, JTB and Lane, DA and Ahnström, J},
doi = {10.1111/jth.14594},
journal = {Journal of Thrombosis and Haemostasis},
title = {The roles of factor Va and protein S in formation of the activated protein C/protein S/factor Va inactivation complex},
url = {http://dx.doi.org/10.1111/jth.14594},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background: Activated protein C (APC)-mediated inactivation of factor (F)Va is greatlyenhanced by protein S. For inactivation to occur, a trimolecular complex between FVa,APC and protein S must form on the phospholipid membrane. However, directdemonstration of complex formation has proven elusive.Objectives:To elucidate the nature of the phospholipid-dependent interactions betweenAPC, protein S and FVa.Methods:We evaluated binding of active site blocked APC to phospholipid-coatedmagnetic beads in the presence and absence of protein S and/or FVa. The importanceof protein S and FV residues were evaluated functionally.Results: APC alone bound weakly to phospholipids. Protein S mildly enhanced APCbinding to phospholipid surfaces, whereas FVa did not. However, FVa together withproteinS enhanced APC binding(>14-fold), demonstrating formation of an APC/proteinS/FVa complex. C4b binding protein-bound protein S failed to enhance APC binding,agreeing with its reduced APC cofactor function. Protein S variants (E36A and D95A)with reduced APC cofactor function exhibited essentially normal augmentation of APCbinding to phospholipids, but diminished APC/protein S/FVa complex formation,suggesting involvement in interactions dependent upon FVa. Similarly, FVaNara(W1920R), an APC resistant FV variant, also did not efficiently incorporate into thetrimolecular complex as efficiently as wild-type FVa. FVa inactivation assays suggestedthat the mutation impairs its affinity for phospholipid membranes and with protein Swithin the complex. Conclusions: FVa plays a central role in the formation of its inactivation complex.Furthermore, membrane proximal interactions between FVa, APC and protein S areessential for its cofactor function.
AU  - Gierula,M
AU  - SallesCrawley,II
AU  - Santamaria,S
AU  - TerazOrosz,A
AU  - Crawley,JTB
AU  - Lane,DA
AU  - Ahnström,J
DO  - 10.1111/jth.14594
PY  - 2019///
SN  - 1538-7933
TI  - The roles of factor Va and protein S in formation of the activated protein C/protein S/factor Va inactivation complex
T2  - Journal of Thrombosis and Haemostasis
UR  - http://dx.doi.org/10.1111/jth.14594
UR  - http://hdl.handle.net/10044/1/72223
ER  -
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