Burke R L, Pachl C, Quiroga M, Rosenberg S, Haigwood N, Nordfang O, Ezban M
J Biol Chem. 1986 Sep 25;261(27):12574-8.
A lack of factor VIII:C, manifested as a bleeding disorder due to the absence of clot formation, is known as hemophilia A, an X chromosome-linked inherited disease afflicting 1-2 males/10,000. To determine the minimum functional domain(s) essential for factor VIII:C activity, we have expressed the amino-terminal (92-kDa) and carboxyl-terminal (80-kDa) proteolytic cleavage products as individual, secreted polypeptides in monkey cells without the 909-residue central region. We have found that neither terminal domain alone is able to promote coagulation in factor VIII:C-deficient plasma. However, when the 92- and 80-kDa peptides are co-expressed, clotting activity is readily detected. Thus, these two chains alone constitute an active or activatable complex. The central domain is required neither for activity nor for the assembly of an active complex from two chains expressed in trans. These results suggest that a truncated derivative of factor VIII:C may be useful in coagulation therapy.
缺乏凝血因子VIII:C会因无法形成凝块而表现为出血性疾病，这被称为甲型血友病，是一种X染色体连锁的遗传性疾病，每10000名男性中有1至2人患病。为了确定凝血因子VIII:C活性所必需的最小功能结构域，我们在没有909个氨基酸残基的中央区域的情况下，在猴细胞中分别表达了氨基末端（92 kDa）和羧基末端（80 kDa）的蛋白水解裂解产物作为单独分泌的多肽。我们发现，单独的任何一个末端结构域都不能促进凝血因子VIII:C缺陷血浆中的凝血作用。然而，当92 kDa和80 kDa的肽共同表达时，很容易检测到凝血活性。因此，仅这两条链就构成了一个活性或可激活的复合物。中央结构域对于活性以及由反式表达的两条链组装活性复合物都不是必需的。这些结果表明，凝血因子VIII:C的截短衍生物可能在凝血治疗中有用。
