<p>This subfamily of <db_xref db="PIRSF" dbkey="PIRSF000354"/> contains coagulation factor VIII, the cofactor of activated factor IX in the factor X-activating complex of the intrinsic coagulation pathway. The structure and function of factor VIII have been reviewed [<cite idref="PUB00027871"/>]. The domain architecture of the precursor molecules can be represented as A1-A2-B-A3-C1-C2. The A domains are diverged versions of the multicopper oxidase domain (<db_xref db="INTERPRO" dbkey="IPR001117"/>). The B domain is highly variable and is removed during activation to yield noncovalently associated heavy and light chains. The C domains (<db_xref db="INTERPRO" dbkey="IPR000421"/>) promote membrane binding.</p> <p>Defects of the human gene, located on the X chromosome, give rise to hemophilia A. Although factor VIII can be expressed in a variety of tissues, most probably hepatocytes are the major source. These large molecules undergo extensive post-translational modification, including both N- and O-linked glycosylation, disulphide bond formation, and sulphation of a particular tyrosine residue. They are cleaved to form a heavy and a light chain that associate in the presence of divalent metal ions. Although one copper ion is bound per molecule, calcium or manganese ions are more efficient in promoting reassociation.</p> <p>As soon as it reaches the blood stream, factor VIII becomes tightly bound to von Willebrand factor, which may prevent premature binding of factor VIII to the factor X-activating complex. Further proteolytic cleavages of factor VIII are required for it to serve as a cofactor that enhances the activity of factor IXa. After initiation of the coagulation cascade, factors IXa and VIIIa form the membrane-bound complex that activates factor X. Factor VIIIa is rapidly inactivated both by dissociation from the complex and by further proteolytic degradation.</p> Coagulation factor VIII