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  • A model describing the inactivation of factor Va by APC: bond cleavage, fragment dissociation, and product inhibition.
  • Hockin MF, Cawthern KM, Kalafatis M, Mann KG
  • Biochemistry , 5/ 1999 , Volume 38 , pages: 6918-6934
  • Department of Biochemistry, The University of Vermont, College of Medicine, Burlington, Vermont 05405, USA.
  • The inactivation of factor Va is a complex process which includes bond cleavage (at three sites) and dissociation of the A2N.A2C peptides, with intermediate activity in each species. Quantitation of the functional consequences of each step in the reaction has allowed for understanding of the presentation of disease in individuals possessing the factor V polymorphism factor VLEIDEN. APC cleavage of membrane-bound bovine factor Va (Arg306, Arg505, Arg662) leads to the dissociation of fragments of the A2 domain, residues 307-713 (A2N.A2C + A2C-peptide), leaving behind the membrane-bound A1.LC species. Evaluation of the dissociation process by light scattering yields invariant mass loss estimates as a function of APC concentration. The rate constant for A2 fragment dissociation varies with [APC], reaching a maximal value of k = 0.028 s-1, the unimolecular rate constant for A2 domain fragment dissociation. The APC binding site resides in the factor Va light chain (LC) (Kd = 7 nM), suggesting that the membrane-bound LC.A1 product would act to sequester APC. This inhibitory interaction (LC.A1.APC) is demonstrated to exist with either purified factor Va LC or the products of factor Va inactivation. Utilizing these experimental data and the reported rates of bond cleavage, binding constants, and product activity values for factor Va partial inactivation products, a model is developed which describes factor Va inactivation and accounts for the defect in factor VLEIDEN. The model accurately predicts the rates of inactivation of factor Va and factor VaLEIDEN, and the effect of product inhibition. Modeled reaction progress diagrams and activity profiles (from either factor Va or factor VaLEIDEN) are coincident with experimentally derived data, providing a mechanistic and kinetic explanation for all steps in the inactivation of normal factor Va and the pathology associated with factor VLEIDEN.
Michael Schubert

Metadata information

PubMed 10346914
Taxonomy Homo sapiens
Gene Ontology blood coagulation
BioModels Database MODEL1108260001
BioModels Database BIOMD0000000365
Human Disease Ontology inherited blood coagulation disease
Curation status
Name Description Size Actions

Model files

BIOMD0000000365_url.xml SBML L2V4 representation of Hockin1999_BloodCoagulation_VaInactivation 46.43 KB Preview | Download

Additional files

BIOMD0000000365.vcml Auto-generated VCML file 66.46 KB Preview | Download
BIOMD0000000365_urn.xml Auto-generated SBML file with URNs 46.07 KB Preview | Download
BIOMD0000000365.svg Auto-generated Reaction graph (SVG) 74.98 KB Preview | Download
BIOMD0000000365.xpp Auto-generated XPP file 7.84 KB Preview | Download
BIOMD0000000365.m Auto-generated Octave file 12.03 KB Preview | Download
BIOMD0000000365.sci Auto-generated Scilab file 10.83 KB Preview | Download
BIOMD0000000365.png Auto-generated Reaction graph (PNG) 304.77 KB Preview | Download
BIOMD0000000365-biopax3.owl Auto-generated BioPAX (Level 3) 81.48 KB Preview | Download
BIOMD0000000365.pdf Auto-generated PDF file 287.63 KB Preview | Download
BIOMD0000000365-biopax2.owl Auto-generated BioPAX (Level 2) 45.63 KB Preview | Download

  • Model originally submitted by : Michael Schubert
  • Submitted: Aug 26, 2011 5:12:01 PM
  • Last Modified: Oct 9, 2014 6:17:13 PM
  • Version: 2 public model Download this version
    • Submitted on: Oct 9, 2014 6:17:13 PM
    • Submitted by: Michael Schubert
    • With comment: Current version of Hockin1999_BloodCoagulation_VaInactivation
  • Version: 1 public model Download this version
    • Submitted on: Aug 26, 2011 5:12:01 PM
    • Submitted by: Michael Schubert
    • With comment: Original import of Hockin1999_BloodCoagulation_VaInactivation
Curator's comment:
(added: 26 Aug 2011, 17:32:30, updated: 26 Aug 2011, 17:32:30)
Reproduction of figure 7a of the article. Model integrated using PySCeS and plotted with Matplotlib.