Factor VIIa: Difference between revisions
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FVIIa alone shows very little proteolytic activity and only becomes fully active when complexed to its obligatory cofactor, tissue factor (TF) and cations, mainly Ca++. TF, located in the vessel wall, is exposed to circulating FVIIa upon injury or some type of stimulus and forms a TF-FVIIa complex. A unique property of TF-FVIIa among other coagulation enzyme complexes is that phospholipids are not an obligate requirement for the assembly of the complex. However, the activity of the complex towards its substrates (FIX and FX) requires a lipid surface which is provided by the membrane-anchored TF. The TF-phospholipid complex enhances the efficiency (kcat/Km) of FVIIa-catalyzed reactions by the 107-fold6. There are four distinct steps that are required for the full activity of the TF-FVIIa complex (Scheme 1: 1) proteolytic activation of single-chained FVII to two-chain disulfide bridged FVIIa 2) binding of Ca++ 3) interaction of TF with FVIIa 4) acidic-membrane association and proper orientation of substrate<ref>PMID:1537862</ref><ref>PMID:18640965</ref>. . | FVIIa alone shows very little proteolytic activity and only becomes fully active when complexed to its obligatory cofactor, tissue factor (TF) and cations, mainly Ca++. TF, located in the vessel wall, is exposed to circulating FVIIa upon injury or some type of stimulus and forms a TF-FVIIa complex. A unique property of TF-FVIIa among other coagulation enzyme complexes is that phospholipids are not an obligate requirement for the assembly of the complex. However, the activity of the complex towards its substrates (FIX and FX) requires a lipid surface which is provided by the membrane-anchored TF. The TF-phospholipid complex enhances the efficiency (kcat/Km) of FVIIa-catalyzed reactions by the 107-fold6. There are four distinct steps that are required for the full activity of the TF-FVIIa complex (Scheme 1: 1) proteolytic activation of single-chained FVII to two-chain disulfide bridged FVIIa 2) binding of Ca++ 3) interaction of TF with FVIIa 4) acidic-membrane association and proper orientation of substrate<ref>PMID:1537862</ref><ref>PMID:18640965</ref>. . | ||
(Add fig 9 from ref 6). | (Add fig 9 from ref 6). | ||
===Structural changes in FVIIa activation=== | |||
====Cation interaction==== | |||
The Gla domain binds seven Ca++ ions arranged in a linear fashion. Ca++ induced changes in the Gla domain are responsible for major structural rearrangements in that region that facilitate binding of FVIIa to membrane<ref>PMID:8844844</ref>. Binding of Ca++ induces an increase in the α-helical content of that region. | |||
====TF interaction==== | |||
The Gla domain also binds to the C-terminal of TF. The interaction is mainly hydrophobic called the “hydrophobic stack”. EGF1 binds a single Ca++ ion and packs into a groove formed by the two modules of TF. This interface is the largest and contributes the most energetically in binding of the cofactor to the protease domain13. EGF2 and the catalytic domain interact with the N-domain of TF. The whole binding epitope of TF to FVIIa looks like a stripe running along the whole length of TF | |||
