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Biochemistry. 2000 Sep 19;39(37):11467-76.

Dimerization of tissue factor supports solution-phase autoactivation of factor VII without influencing proteolytic activation of factor X.

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1
Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Abstract

Tissue factor (TF) is a transmembrane receptor that initiates the thrombogenic cascade by assembly with the serine protease factor VII or VIIa (VII/VIIa) resulting in formation of the bimolecular active complex TF.VIIa. Chemical cross-linking studies identified that a minor population of TF forms dimers on the surface of cells, possibly influencing TF.VIIa proteolytic function as a result of dimerization. We here investigate the effects of dimerization of the extracellular domain of TF on the proteolytic function of the TF. VIIa complex. The leucine zipper dimerization domain of the yeast transcriptional factor GCN4 (LZ) was genetically fused at the C-terminus of the extracellular domain of TF separated by a short linker (TF(L)LZ). TF(L)LZ homodimerized with a K(d) similar to that of the LZ peptide. Tryptophan fluorescence indicated that the two TF moieties were in close proximity and parallel orientation in TF(L)LZ. TF(L)LZ dimers bound two molecules of VIIa, and VIIa binding did not influence the TF dimer equilibrium. Dimerization influenced neither amidolytic nor the factor X activation activities of the TF. VIIa complexes. Notably, dimer TF(L)LZ efficiently promoted the autoactivation of VII to VIIa in solution in contrast to monomeric TF(L)LZ or TF(1)(-)(218). Thus, TF dimerization on cells may serve to "prime" the initiation of the coagulation pathway by generating active TF.VIIa complexes for the subsequent activation of downstream macromolecular substrates.

PMID:
10985793
[Indexed for MEDLINE]
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