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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1240-1247.
Prepublished online as a Blood First Edition Paper on October 26, 2007November 1, 2007; DOI 10.1182/blood-2007-08-109918.
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Submitted August 30, 2007
Accepted October 24, 2007
The tertiary structure and domain organization of coagulation factor VIII
Betty W. Shen, Paul Clint Spiegel, Chong-Hwan Chang, Jae-Wook Huh, Jung-Sik Lee, Jeanman Kim, Young-Ho Kim, and Barry L Stoddard*
Program in Molecular Biophysics, Structure & Design, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Central Research Institute, Green Cross Corporation, Yongin, Korea, Republic of
Department of Life Sciences, The University of Suwon, Kyongi-do, Korea, Republic of
* Corresponding author; email: bstoddar{at}fhcrc.org.
Factor VIII (fVIII) is a serum protein in the coagulation cascade that nucleates the assembly of a membrane-bound protease complex on the surface of activated platelets at the site of a vascular injury. Hemophilia A is caused by a variety of mutations in the factor VIII gene and typically requires replacement therapy with purified protein. We have determined the structure of a fully active, recombinant form of factor VIII (r-fVIII), which consists of a heterodimer of peptides, respectively containing the A1-A2 and A3-C1-C2 domains. The structure permits unambiguous modeling of the relative orientations of the five domains of r-fVIII. Comparison of the structures of factor VIII, factor V and ceruloplasmin indicates that the location of bound metal ions and of glycosylation, both of which are critical for domain stabilization and association, overlap at some positions but have diverged at others.
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