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

@article{Esmon1995ThrombomodulinAA,
  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},
  year={1995},
  volume={9},
  pages={946 - 955}
}
  • C. Esmon
  • Published 1 July 1995
  • Chemistry, Medicine
  • 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… Expand
Structural basis for the anticoagulant activity of the thrombin–thrombomodulin complex
TLDR
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. Expand
Thrombomodulin structure and function.
  • J. Sadler
  • Biology, Medicine
  • Thrombosis and haemostasis
  • 1997
TLDR
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. Expand
Activation of Thrombin-activable Fibrinolysis Inhibitor Requires Epidermal Growth Factor-like Domain 3 of Thrombomodulin and Is Inhibited Competitively by Protein C*
TLDR
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. Expand
Chapter 9 - Thrombin receptors
Thrombin is a multifunctional serine protease that is distinctly unique among coagulation proteins, possessing both procoagulant and anticoagulant properties.1 These properties bestow upon thrombin aExpand
Zymogen and activated protein C have similar structural architecture
TLDR
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. Expand
TAFI, or Plasma Procarboxypeptidase B, Couples the Coagulation and Fibrinolytic Cascades through the Thrombin-Thrombomodulin Complex*
TLDR
TAFI in vitro and possibly in vivo defines an explicit molecular connection between the coagulation and fibrinolytic cascades, such that expression of activity in the former down-regulates the activity of the latter. Expand
Role of the activation peptide in the mechanism of protein C activation
TLDR
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. Expand
Covalently immobilized thrombomodulin inhibits coagulation and complement activation of artificial surfaces in vitro.
TLDR
It is concluded that the suggested method for preparation of TM immobilization may serve to prepare model substrates for studies on TM interactions but similarly provides a promising coating strategy for blood contacting medical devices. Expand
Natural Anticoagulants and Their Pathways
TLDR
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. Expand
Thrombin Activatable Fibrinolysis Inhibitor and an Antifibrinolytic Pathway
  • L. Bajzar
  • Chemistry, Medicine
  • Arteriosclerosis, thrombosis, and vascular biology
  • 2000
TLDR
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. Expand
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TLDR
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. Expand
The active site of thrombin is altered upon binding to thrombomodulin. Two distinct structural changes are detected by fluorescence, but only one correlates with protein C activation.
TLDR
The structural change far from Ser-195 was only elicited by thrombomodulin species that stimulate thrombin-dependent activation of protein C, and no fluorescence changes were observed when the fluorescein and ANSThrombin derivatives were titrated with GF5-6. Expand
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TLDR
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TLDR
The structural domains of protein C involved in its interaction with thrombin-thrombomodulin on the endothelial cell surface have been investigated using isolated intact domains of bovine protein C produced from controlled proteolytic digests of the protein, and indicate that the Gla-EGF fragment alone accounts for most of the binding energy of intact protein C for IIa-TM. Expand
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TLDR
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. Expand
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TLDR
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Thrombomodulin is a cofactor for thrombin degradation of recombinant single-chain urokinase plasminogen activator "in vitro" and in a perfused rabbit heart model.
TLDR
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. Expand
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