Horseshoe crab coagulogen is an invertebrate protein with a nerve growth factor-like domain

The rapid clotting of the horseshoe crab hemolymph is essential for both its host defense and hemostasis. It is mediated by the clotting cascade system which consists of four serine proteinase zymogens and the clottable protein coagulogen. Coagulogen, the target protein of the cascade, is converted to an insoluble gel upon activation of the cascade, giving rise to clot formation. Thus this cascade is reminiscent of the mammalian blood coagulation leading to fibrin clot. The structural analysis of coagulogen revealed a polypeptide fold and disulfide bridge pattern in the C-terminal half of the molecule very similar to nerve growth factor (NGF). This finding assigns coagulogen as the first structurally characterized invertebrate protein which belongs to the cystine knot superfamily. The putative structural similarity of coagulogen and the Drosophila morphogen Spaetzle as well as the homology of its processing proteinases suggests a common origin of the two functionally different cascades. This would exemplify a divergent evolution of two proteinase cascades having totally different functions from common ancestors in a long history of evolution.