on April 28, 2005
Published online before print April 28, 2005, doi: 10.1161/01.ATV.0000168421.13467.82
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on January 28, 2005
Accepted on April 18, 2005
Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway. Novel Insights Into Structure-Function Relationships and Molecular Recognition
Björn Dahlbäck * and Bruno O. Villoutreix
From the Department of Laboratory Medicine (B.D.), Clinical Chemistry, Lund University, The Wallenberg Laboratory, University Hospital, Malmö, Sweden; and INSERM U648 (B.O.V.), University of Paris V, Paris, France.
* To whom correspondence should be addressed. E-mail: bjorn.dahlback{at}klkemi.mas.lu.se.
Abstract--The protein C system provides important control of blood coagulation by regulating the activities of factor VIIIa (FVIIIa) and factor Va (FVa), cofactors in the activation of factor X and prothrombin, respectively. The system comprises membrane-bound and circulating proteins that assemble into multi-molecular complexes on cell surfaces. Vitamin K-dependent protein C, the key component of the system, circulates in blood as zymogen to an anticoagulant serine protease. It is efficiently activated on the surface of endothelial cells by thrombin bound to the membrane protein thrombomodulin. The endothelial protein C receptor (EPCR) further stimulates the protein C activation. Activated protein C (APC) together with its cofactor protein S inhibits coagulation by degrading FVIIIa and FVa on the surface of negatively charged phospholipid membranes. Efficient FVIIIa degradation by APC requires not only protein S but also intact FV, which like thrombin is a Janus-faced protein with both procoagulant and anticoagulant potential. In addition to its anticoagulant properties, APC has antiinflammatory and antiapoptotic functions, which are exerted when APC binds to EPCR and proteolytic cleaves protease-activated receptor 1 (PAR-1). The protein C system is physiologically important, and genetic defects affecting the system are the most common risk factors of venous thrombosis. The proteins of the protein C system are composed of multiple domains and the 3-dimensional structures of several of the proteins are known. The molecular recognition of the protein C system is progressively being unraveled, giving us new insights into this fascinating and intricate molecular scenario at the atomic level.
Key words: factor V • protein C • protein S • thrombomodulin
This article has been cited by other articles:
 |
|
 |
|
  L. O. Mosnier, A. Zampolli, E. J. Kerschen, R. A. Schuepbach, Y. Banerjee, J. A. Fernandez, X. V. Yang, M. Riewald, H. Weiler, Z. M. Ruggeri, et al. Hyperantithrombotic, noncytoprotective Glu149Ala-activated protein C mutant Blood, June 4, 2009; 113(23): 5970 - 5978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sood, L. Sholl, B. Isermann, M. Zogg, S. R. Coughlin, and H. Weiler Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin Blood, August 1, 2008; 112(3): 585 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Steen, S. Tran, L. Autin, B. O. Villoutreix, A.-L. Tholander, and B. Dahlback Mapping of the Factor Xa Binding Site on Factor Va by Site-directed Mutagenesis J. Biol. Chem., July 25, 2008; 283(30): 20805 - 20812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Dahlback Advances in understanding pathogenic mechanisms of thrombophilic disorders Blood, July 1, 2008; 112(1): 19 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Berny, T. C. White, E. I. Tucker, L. A. Bush-Pelc, E. Di Cera, A. Gruber, and O. J.T. McCarty Thrombin Mutant W215A/E217A Acts as a Platelet GPIb Antagonist Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 329 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. O. Mosnier, X. V. Yang, and J. H. Griffin Activated Protein C Mutant with Minimal Anticoagulant Activity, Normal Cytoprotective Activity, and Preservation of Thrombin Activable Fibrinolysis Inhibitor-dependent Cytoprotective Functions J. Biol. Chem., November 9, 2007; 282(45): 33022 - 33033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Borgel, C. Bornstain, P. H. Reitsma, N. Lerolle, S. Gandrille, F. Dali-Ali, C. T. Esmon, J.-Y. Fagon, M. Aiach, and J.-L. Diehl A Comparative Study of the Protein C Pathway in Septic and Nonseptic Patients with Organ Failure Am. J. Respir. Crit. Care Med., November 1, 2007; 176(9): 878 - 885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Kerschen, J. A. Fernandez, B. C. Cooley, X. V. Yang, R. Sood, L. O. Mosnier, F. J. Castellino, N. Mackman, J. H. Griffin, and H. Weiler Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C J. Exp. Med., October 1, 2007; 204(10): 2439 - 2448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Segers, O. Sperandio, M. Sack, R. Fischer, M. A. Miteva, J. Rosing, G. A. F. Nicolaes, and B. O. Villoutreix Design of protein membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V PNAS, July 31, 2007; 104(31): 12697 - 12702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Danese, E. Dejana, and C. Fiocchi Immune Regulation by Microvascular Endothelial Cells: Directing Innate and Adaptive Immunity, Coagulation, and Inflammation J. Immunol., May 15, 2007; 178(10): 6017 - 6022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. O. Mosnier, B. V. Zlokovic, and J. H. Griffin The cytoprotective protein C pathway Blood, April 15, 2007; 109(8): 3161 - 3172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. O. Mosnier and B. N. Bouma Regulation of Fibrinolysis by Thrombin Activatable Fibrinolysis Inhibitor, an Unstable Carboxypeptidase B That Unites the Pathways of Coagulation and Fibrinolysis Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2445 - 2453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Peters, W. Ning, T. J. Chu, C. J. Li, and A. M. K. Choi Comparative SAGE analysis of the response to hypoxia in human pulmonary and aortic endothelial cells Physiol Genomics, September 14, 2006; 26(2): 99 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Feistritzer, R. A. Schuepbach, L. O. Mosnier, L. A. Bush, E. Di Cera, J. H. Griffin, and M. Riewald Protective Signaling by Activated Protein C Is Mechanistically Linked to Protein C Activation on Endothelial Cells J. Biol. Chem., July 21, 2006; 281(29): 20077 - 20084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Heistad Oxidative Stress and Vascular Disease: 2005 Duff Lecture Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 689 - 695. [Abstract] [Full Text] [PDF]
|
|