Activation peptides prolong the murine plasma half-life of human factor VII.
Coagulation factors VII (FVII), IX (FIX), X (FX), and protein C share the same domain organization but display very different plasma half-lives. It is plausible that the half-life is influenced by the activation peptide, differing in length and glycosylation and missing in FVII. To test this hypothesis, the influence of activation peptides on the plasma half-life of human FVII was studied by administering human FVII variants containing activation peptide motifs to mice. Insertion of the activation peptide from FX gave 4-fold longer terminal half-life (5.5 hours vs 1.4 hours for FVII), whereas the activation peptide from FIX and protein C resulted in half-lives of 4.3 and 1.7 hours, respectively. Using FX's activation peptide we identified the N-linked glycans as structural features important for the half-life. The peptide location within the FVII molecule appeared not to be critical because similar prolongation was obtained with the activation peptide inserted immediately before the normal site of activation and at the C-terminus. However, only the latter variant was activatable, yielding full amidolytic activity and reduced proteolytic activity with preserved long half-life. Our data support that activation peptides function as plasma retention signals and constitute a new manner to extend the half-life of FVII(a).
Haemostasis Biochemistry, Novo Nordisk A/S, Måløv, Denmark.
Linda
L
Johansson
Ditte M
DM
Karpf
Lene
L
Hansen
Hermann
H
Pelzer
Egon
E
Persson
D020816:Amino Acid Motifs; D000818:Animals; D005164:Factor IX / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics; D005167:Factor VII / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D005170:Factor X / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000276:immunology / Q000493:pharmacokinetics / Q000502:physiology*; D010949:Plasma / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
D050505:Mutant Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; C047135:protein C activator peptide; D005167:Factor VII; D005164:Factor IX; D005170:Factor X