Calcium-binding EGF-like modules in coagulation proteinases: function of the calcium ion in module interactions

Epidermal growth factor (EGF)-like modules are involved in protein-protein interactions and are found in numerous extracellular proteins and membrane proteins. Among these proteins are enzymes involved in blood coagulation, f ibrinolysis and the complement system as well as matrix proteins and cell s urface receptors such as the EGF precursor, the low density lipoprotein rec eptor and the developmentally important receptor, Notch. The coagulation en zymes, factors VII, IX and X and protein C, all have two EGF-like modules, whereas the cofactor of activated protein C, protein S, has four EGF-like m odules in tandem. Certain of the cell surface receptors have numerous EGF m odules in tandem. A subset of EGF modules bind one Ca2+. The Ca2+-binding s equence motif is coupled to a sequence motif that brings about beta-hydroxy lation of a particular Asp/Asn residue. Ca2+-binding to an EGF module is im portant to orient neighboring modules relative to each other in a manner th at is required for biological activity. The Ca2+ affinity of an EGF module is often influenced by its N-terminal neighbor, be it another EGF module or a module of another type. This can result in an increase in Ca2+ affinity of several orders of magnitude. Point mutations in EGF modules that involve amino acids which are Ca2+ ligands result in the biosynthesis of biologica lly inactive proteins. Such mutations have been identified, for instance, i n factor IX, causing hemophilia B, in fibrillin, causing Marfan syndrome, a nd in the low density lipoprotein receptor, causing hypercholesterolemia. I n this review the emphasis will be on the coagulation factors. (C) 2000 Els evier Science B.V. All rights reserved.