Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface

  title={Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface},
  author={Charles T. Esmon},
  journal={The FASEB Journal},
  pages={946 - 955}
  • C. Esmon
  • Published 1 July 1995
  • Biology, Chemistry
  • The FASEB Journal
The protein C anticoagulant system generates an “on demand” physiologic anticoagulant response. The pathway is initiated when thrombin binds to the endothelial cell thrombin binding protein, thrombomodulin. The complex exhibits dramatically altered macromolecular specificity. It rapidly cleaves the protein C zymogen to form the anticoagulant, activated protein C. Complex formation between thrombin and thrombomodulin also prevents thrombin, the enzyme responsible for clot formation and a potent… 

Structural basis for the anticoagulant activity of the thrombin–thrombomodulin complex

Docking of a protein C model to thrombin–TME456 indicates that TME45 may bind substrates in such a manner that their zymogen-activation cleavage sites are presented optimally to the unaltered thrombomodulin active site.

Thrombomodulin structure and function.

  • J. Sadler
  • Biology, Chemistry
    Thrombosis and haemostasis
  • 1997
The structure of EGF-like domain 4 has been determined by NMR spectroscopy, and the structure of a complex between thrombin and a peptide from thrombomodulin EGF -like domain 5 was determined by X-ray crystallography, small steps toward an understanding of how throm bomodoxin regulates throm bin.

Activation of Thrombin-activable Fibrinolysis Inhibitor Requires Epidermal Growth Factor-like Domain 3 of Thrombomodulin and Is Inhibited Competitively by Protein C*

The anticoagulant and antifibrinolytic cofactor activities of thrombomodulin have distinct structural requirements: protein C binding to the thrombin-thrombumodulin complex requires EGF-like domain 4, whereas TAFI binding also requires E GF-likedomain 3.

Zymogen and activated protein C have similar structural architecture

The new structural features reported here for protein C have general relevance to vitamin K-dependent clotting factors containing epidermal growth factor domains, such as factors VII, IX, and X.

Role of the activation peptide in the mechanism of protein C activation

It is demonstrated that the peculiar clustering of acidic residues increases the intrinsic disorder propensity of the activation peptide and adversely affects the rate of activation, and an important H-bond between residues T176 and Y226 is identified that is critical to transduce the inhibitory effect of Ca 2+ and the stimulatory effect of thrombomodulin on the rates of activation.

Natural Anticoagulants and Their Pathways

Blood coagulation is a complex process involving blood cell surfaces, plasma proteins, and inhibitory mechanisms, the most important of which are thought to include the tissue factor pathway inhibitor and the protein C anticoagulant mechanisms.

Thrombin Activatable Fibrinolysis Inhibitor and an Antifibrinolytic Pathway

  • L. Bajzar
  • Biology
    Arteriosclerosis, thrombosis, and vascular biology
  • 2000
A historical account of efforts to isolate TAFI and characterize it with respect to its activation, activity, regulation, and potential function in vivo is encompassed.

Enhanced Protein C Activation and Inhibition of Fibrinogen Cleavage by a Thrombin Modulator

It was shown that LY254603 mediates the change in enzymatic substrate specificity through an alteration in thrombin's S3 substrate recognition site, a mechanism that appeared to be independent of allosteric changes induced by either sodium ions or by thrombomodulin.



Enhancing protein C interaction with thrombin results in a clot-activated anticoagulant

It is shown that this 'preform' of protein C, unlike the natural circulating zymogen, can be activated by thrombin generated in clotting human plasma, resulting in an inhibition of further clot formation and engineered a site-activated agent, which only has anticoagulant activity when significant amounts of throm bin are being generated.

Molecular events that control the protein C anticoagulant pathway.

  • C. Esmon
  • Biology, Chemistry
    Thrombosis and haemostasis
  • 1993
To determine whether the models derived from attempts at the molecular analysis of the protein C activation complex are at all relevant to the other coagulation complexes will require further examination, the concept that residues near the cleavage site contact residues in the free enzyme in an unfavorable fashion is a hypothesis that is directly testable for all of the complexes.

Regulation of blood coagulation by the protein C system

  • F. WalkerP. Fay
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 1992
Protein G is a plasma, vitamin K‐dependent zymogen of a serine protease that can inhibit blood coagulation and the importance of this pathway is seen in the occurrence of thrombosis in individuals with deficiencies in elements of the pathway like protein G and protein S.

Thrombomodulin: an anticoagulant cell surface proteoglycan with physiologically relevant glycosaminoglycan moiety.

The structure/function relationships of TM are summarized indicating that a major O-linked glycan moiety of the thrombin receptor acts as main modulator of receptor function, and the central role of TM as anticoagulant cofactor is demonstrated.

Single amino acid substitutions dissociate fibrinogen-clotting and thrombomodulin-binding activities of human thrombin.

The results demonstrate that thrombins with predominantly anticoagULant or procoagulant activity can be created by mutagenesis and that thROMbomodulin- and fibrinogen-binding sites on thrombin may overlap but are not identical.

Crystallographic structures of thrombin complexed with thrombin receptor peptides: existence of expected and novel binding modes.

Eight crystal structures of thrombin complexed with receptor-based peptides are determined and a comparison of receptor density to the responsiveness of a cell did not support a role for receptor oligomerization in signaling, suggesting a novel alternative mode of receptor peptide-thrombin interaction.

Human protein C inhibits selectin-mediated cell adhesion: role of unique fucosylated oligosaccharide.

It is shown that both human plasma-derived and human cell-produced recombinant Protein C inhibit E- Selectin-mediated cell adhesion, and a polylactosamine structural determinant is defined that appears to be a more potent ligand for E-selectin than the sialylated Lewis X antigen.

Thrombomodulin is a cofactor for thrombin degradation of recombinant single-chain urokinase plasminogen activator "in vitro" and in a perfused rabbit heart model.

It is postulate that the amino-terminal sequence of rscu-PA, containing the epidermal growth factor-like and the kringle domains is involved in the cofactor effect of thrombomodulin on scU-PA inactivation by thrombin, and concludes that a regulatory mechanism of scu- PA inactivation is present at the cell surface.