A1 Subunit-mediated Regulation of Thrombin-activated Factor Viii A2 Subunit Dissociation.
From: Aflac Cancer Center and Blood Disorders Service, Children’s Healthcare of Atlanta, Georgia 30322, USA.
The Journal of biological chemistry
- Publish Date: May 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 20
- Pages: 13922-30
- Medium: Print
- Language: English
- Citation (JAMA): Parker Ernest T, Doering Christopher B, Lollar Pete, et al. A1 Subunit-mediated Regulation of Thrombin-activated Factor Viii A2 Subunit Dissociation.. J. Biol. Chem. May 2006;281:13922-30
Abstract
Factor VIII (fVIII) is the plasma protein that is missing or deficient in hemophilia A. In contrast, elevated levels of fVIII are associated with an increased risk of arterial and venous thrombosis. fVIII is activated by thrombin to form a non-covalently linked A1/A2/A3-C1-C2 heterotrimer. At physiological concentrations, fVIIIa decays as a result of A2 subunit dissociation, which may help regulate the balance between hemostasis and thrombosis. A2 subunit dissociation is faster in human fVIIIa than in porcine fVIIIa, which may represent an evolutionary adaptation associated with the development of the upright posture and venous stasis in the lower extremities. To investigate the basis for the different decay kinetics of human and porcine fVIIIa, hybrid fVIII molecules representing all possible combinations of human and porcine A domains were isolated. The kinetics of fVIIIa decay were measured and fit to a model describing a reversible bimolecular reaction in which the dissociation rate constant, k, and dissociation constant, Kd, were the fitted parameters. Substitution of the porcine A1 domain into human fVIIIa produced a dissociation rate constant indistinguishable from porcine fVIIIa. Subsequently, substitution of the second cupredoxin-like A1 subdomain resulted in a dissociation rate constant similar to porcine fVIIIa, whereas substitution of the first cupredoxin-like A1 subdomain resulted in a dissociation rate constant intermediate between human and porcine fVIIIa. We propose that cupredoxin-like A1 subdomains in fVIII contain inter-species differences that are a result of selective pressure on the dissociation rate constant.
Mesh Headings (Keywords): Animals, Factor VIIIa, Humans, Kinetics, Models, Chemical, Protein Binding, Protein Structure, Tertiary, Recombinant Proteins, Risk, Species Specificity, Swine, Temperature, Thrombin
Check for Full Text / PubMed Unique Identifier (PMID): 16513639
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.