The tertiary structure and domain organization of coagulation factor VIII

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 r...

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Bibliographic Details
Published in:Blood 2008-02, Vol.111 (3), p.1240-1247
Main Authors: Shen, Betty W., Spiegel, Paul Clint, Chang, Chong-Hwan, Huh, Jae-Wook, Lee, Jung-Sik, Kim, Jeanman, Kim, Young-Ho, Stoddard, Barry L.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
CHO Cells
Cricetinae
Cricetulus
Dimerization
Factor VIII - chemistry
Factor VIII - genetics
Factor VIII - metabolism
Glycosylation
Hematologic and hematopoietic diseases
Hemostasis, Thrombosis, and Vascular Biology
Medical sciences
Models, Molecular
Protein Binding
Protein Structure, Quaternary
Protein Structure, Tertiary
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Summary: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 5 domains of r-fVIII. Comparison of the structures of fVIII, fV, 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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-08-109918