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A peptide derived from a tissue factor loop region functions as a tissue factor--factor VIIa antagonist
L R Paborsky1, V S Law, C T Mao
1Gilead Sciences, Inc., Foster City, California 94404, USA.
Biochemistry
|November 21, 1995
Summary
This study identifies key residues in tissue factor (TF) crucial for binding factor VIIa (FVIIa), advancing our understanding of blood coagulation initiation. These findings refine the map of the FVIIa binding site on TF.
Area of Science:
- Biochemistry
- Molecular Biology
- Hematology
Background:
- Tissue factor (TF) initiates blood coagulation by binding factor VIIa (FVIIa).
- TF is a transmembrane protein and a member of the class 2 cytokine receptor superfamily.
- The extracellular domain of TF comprises two immunoglobulin-like domains.
Purpose of the Study:
- To map the FVIIa binding site on TF by alanine-scanning mutagenesis.
- To identify specific TF residues critical for FVIIa cofactor function.
Main Methods:
- Alanine-scanning mutagenesis of the extracellular domain of TF.
- Screening of TF mutants for their ability to enhance FVIIa activity.
Main Results:
- The FVIIa binding site is discontinuous, located at the domain-domain interface.
- Residues D44, W45, and K46 in a TF loop are important for FVIIa interaction.
- Five additional residues in flanking beta-strands (Y34, Q37, I38, K48, Y51) are critical for TF cofactor function.
Conclusions:
- Specific residues within TF beta-strands and loop regions are essential for FVIIa binding and cofactor activity.
- These findings refine the understanding of the TF-FVIIa interaction mechanism.
- This research contributes to the structural and functional characterization of TF in hemostasis.