The life cycle of coagulation factor VIII in view of its structure and function
PJ Lenting, JA Van Mourik… - Blood, The Journal of the …, 1998 - ashpublications.org
PJ Lenting, JA Van Mourik, K Mertens
Blood, The Journal of the American Society of Hematology, 1998•ashpublications.orgTHE PAST TWO DECADES have brought remarkable progress in our understanding of the
molecular basis of hemophilia A. This disease, which has already been documented as a
familial bleeding tendency in the fifth century, 1 still persists as the most common
hemorrhagic disorder, affecting 1 in approximately 5,000 males. 2 Hemophilia has been
associated with deficiency of a plasma component since 1937, when Patek and Taylor3
showed that the clotting defect of hemophilic plasma could be corrected by plasma of a …
molecular basis of hemophilia A. This disease, which has already been documented as a
familial bleeding tendency in the fifth century, 1 still persists as the most common
hemorrhagic disorder, affecting 1 in approximately 5,000 males. 2 Hemophilia has been
associated with deficiency of a plasma component since 1937, when Patek and Taylor3
showed that the clotting defect of hemophilic plasma could be corrected by plasma of a …
THE PAST TWO DECADES have brought remarkable progress in our understanding of the molecular basis of hemophilia A. This disease, which has already been documented as a familial bleeding tendency in the fifth century, 1 still persists as the most common hemorrhagic disorder, affecting 1 in approximately 5,000 males. 2 Hemophilia has been associated with deficiency of a plasma component since 1937, when Patek and Taylor3 showed that the clotting defect of hemophilic plasma could be corrected by plasma of a normal individual. This component was called ‘‘antihemophilic factor,’’or ‘‘factor VIII’’according to the more recent nomenclature. Subsequent studies using preparations enriched in factor VIII activity have established factor VIII as being the cofactor of activated factor IX in the factor X–activating complex of the intrinsic coagulation pathway. 4 However, the molecular entity of factor VIII has remained unidentified until the early 1980s, when the protein was purified to complete homogeneity, and its cDNA was cloned. 5-8 This breakthrough has triggered numerous studies on the genetic and molecular basis of hemophilia A, and consequently our knowledge on the structure and function of the factor VIII protein has been rapidly expanding since then. The present review focuses on the ‘‘life cycle’’of factor VIII, which comprises the sequence of events between biosynthesis and clearance of the protein (see Fig 1). These processes are discussed in view of our current knowledge on factor VIII structure and function, with particular reference to the proteolytic modulation of factor VIII, and its assembly into the factor X activating complex.
BIOSYNTHESIS AND SECRETION OF FACTOR VIII Factor VIII gene. The gene of factor VIII is located at the tip of the long arm of the X chromosome. 5 It spans over 180 kb, and as such is one of the largest genes known. Its transcription may require several hours assuming a transcription rate of 10 nucleotides per second, and yields a 9-kb mRNA product. 5 The factor VIII gene comprises 26 exons, which encode a polypeptide chain of 2351 amino acids. 6-8 This includes a signal peptide of 19 and a mature protein of 2332 amino acids. Analysis of the deduced primary structure determined from the cloned factor VIII cDNA showed the presence of a discrete domain structure: A1-a1-A2-a2-B-a3-A3-C1-C26-8 (Fig 2). The A domains display approximately 30% homology to each other. These domains further display a similar extent of homology to the copper-binding protein ceruloplasmin and to factor V, the
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