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J. Biol. Chem., Vol. 281, Issue 20, 13922-13930, May 19, 2006

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A1 Subunit-mediated Regulation of Thrombin-activated Factor VIII A2 Subunit Dissociation^*

From the Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, and the Department of Pediatrics, Emory University, Atlanta, Georgia 30322

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, K_d, 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.

Received for publication, December 8, 2005 , and in revised form, March 1, 2006.

^* This work was supported by National Institutes of Health Grant R01-HL40921 (to P. L.), by a Bayer Hemophilia Award (to P. L.), and by Hemophilia of Georgia, Inc. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Rm. 416D, Emory Children's Center, 2015 Uppergate Dr., Atlanta, GA 30322. Tel.: 404-727-5569; Fax: 404-727-4859; E-mail: jlollar{at}emory.edu.

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