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Related Experiment Videos

The tissue factor region that interacts with substrates factor IX and Factor X.

D Kirchhofer1, M T Lipari, P Moran

  • 1Departments of Cardiovascular Research and Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA. dak@gene.com

Biochemistry
|June 20, 2000
PubMed
Summary

Researchers identified key areas on tissue factor (TF) crucial for activating coagulation factors. This discovery sheds light on the intricate protein interactions governing blood clotting and potential therapeutic targets.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hematology

Background:

  • Coagulation factor VIIa (FVIIa) enzymatic activity is regulated by its cofactor, tissue factor (TF).
  • TF binds FVIIa with high affinity and is involved in substrate interaction via its C-terminal fibronectin type III domain.

Purpose of the Study:

  • To precisely map the surface-exposed residues in the C-terminal TF domain critical for substrate activation.
  • To elucidate the specific TF region involved in the interaction with coagulation factors IX and X.

Main Methods:

  • Expression of soluble TF (sTF) mutants in E. coli.
  • Assay of sTF mutant ability to support FVIIa-dependent substrate activation using phospholipid vesicles or SW-13 cell membranes.

Main Results:

Related Experiment Videos

  • Factor IX and X interact with a TF region near the phospholipid binding site.
  • A main interaction region (Tyr157-Tyr185) and an extended region (including Asn199, Arg200, Asp204) were identified.
  • TF residues near the FVIIa gamma-carboxyglutamic acid (Gla) domain and a net positive charge on the substrate interaction surface suggest charge-driven binding.

Conclusions:

  • A specific, positively charged surface patch on TF is vital for substrate interaction, distinct from the FVIIa binding site.
  • This detailed mapping provides insights into the molecular mechanisms of blood coagulation and potential targets for anticoagulant therapies.