Factor VIIa
FVIIaFVIIa
IntroductionIntroduction
Factor VIIa (FVIIa)is a single chain trypsin-like serine protease (EC 3.4.21.21) of 406 residues. The FVII[1] zymogen is a glycoprotein consisting of an amino-terminal (N-linked) γ-carboxyglutamic acid (Gla) domain followed by two epidermal growth factor-like (EGF) domains, a short linker peptide, and a carboxy terminal serine protease domain (Figure 1)[1]. The active form, FVIIa, is generated by a specific cleavage of a peptide bond between Arg-152 and Ile-153 at the end of the linker peptide by either factor Xa (FXa) or thrombin (IIa). This cleavage generates an N-terminal light chain of 152 residues linked to a heavy chain of 254 residues by a disulfide bridge [2]. Following cleavage the newly formed N-terminal inserts itself into a cavity, or the activation pocket, forming a salt bridge with Asp343 (Asp194 trypsin numbering).Formation of this salt bridge allows for the maturation of FVIIa to its active form.
FVIIa mechanismFVIIa mechanism
GeneralGeneral
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[3][4]. . (Add fig 9 from ref 6).
BACE1 (β-site of APP cleaving enzyme) also called β-Secretase and memapsin-2 is a 52 kD class I transmembrane aspartic acid protease that cleaves the Amyloid Precursor Protein (APP) in a rate limiting step that contributes to the accumulation of β-amyloid plaques in Alzheimer’s disease (AD). A subsequent cleavage by γ-secretase generates a 40 or 42 amino acid β-amyloid peptide. These peptides can form Aβ plaques that may have deleterious effects on neuronal function and contribute to pathologies of AD. Under normal conditions, BACE1 activity generates a monomeric and soluble Aβ peptide that may play a physiological role in decreasing excitotoxicity and neurotransmission at glutamatergic synapses. Additionally, α-secretase and γ-secretase cleave APP to generate p3 and the carboxy terminal fragment AICD in a non-amyloidogenic pathway. In AD, amyloidogenic pathways become preferential over non-amyloidogenic and Aβ plaques appear under increased levels of BACE1 catalytic activity.
ReferencesReferences
- ↑ Pike AC, Brzozowski AM, Roberts SM, Olsen OH, Persson E. Structure of human factor VIIa and its implications for the triggering of blood coagulation. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8925-30. PMID:10430872
- ↑ Bajaj SP, Rapaport SI, Brown SF. Isolation and characterization of human factor VII. Activation of factor VII by factor Xa. J Biol Chem. 1981 Jan 10;256(1):253-9. PMID:6778860
- ↑ Lawson JH, Butenas S, Mann KG. The evaluation of complex-dependent alterations in human factor VIIa. J Biol Chem. 1992 Mar 5;267(7):4834-43. PMID:1537862
- ↑ Bjelke JR, Olsen OH, Fodje M, Svensson LA, Bang S, Bolt G, Kragelund BB, Persson E. Mechanism of the Ca2+-induced enhancement of the intrinsic factor VIIa activity. J Biol Chem. 2008 Sep 19;283(38):25863-70. Epub 2008 Jul 17. PMID:18640965 doi:10.1074/jbc.M800841200