Factor VIIa: Difference between revisions
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===Factor VIIa=== | ===Factor VIIa=== | ||
==FVIIa== | |||
===Introduction=== | ===Introduction=== | ||
Factor VIIa (FVIIa)is a single chain trypsin-like serine protease (EC 3.4.21.21) of 406 residues. The FVII[http://en.wikipedia.org/wiki/Factor_VIIa] 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)<ref>PMID:10430872</ref>. 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 <ref>PMID:6778860</ref>. 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. | Factor VIIa (FVIIa)is a single chain trypsin-like serine protease (EC 3.4.21.21) of 406 residues. The FVII[http://en.wikipedia.org/wiki/Factor_VIIa] 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)<ref>PMID:10430872</ref>. 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 <ref>PMID:6778860</ref>. 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 as a serine protease== | |||
===FVIIa as a serine protease=== | |||
FVIIa alone is not very efficient in the insertion of the peptide, however, upon binding to TF the process becomes very efficient. The insertion of the N-terminus, therefore, facilitates the formation of both the S1 recognition pocket and the oxyanion hole. | FVIIa alone is not very efficient in the insertion of the peptide, however, upon binding to TF the process becomes very efficient. The insertion of the N-terminus, therefore, facilitates the formation of both the S1 recognition pocket and the oxyanion hole. | ||
Revision as of 19:48, 22 April 2010
Factor VIIaFactor 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 as a serine proteaseFVIIa as a serine protease
FVIIa as a serine proteaseFVIIa as a serine protease
FVIIa alone is not very efficient in the insertion of the peptide, however, upon binding to TF the process becomes very efficient. The insertion of the N-terminus, therefore, facilitates the formation of both the S1 recognition pocket and the oxyanion hole.
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