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Critical Reviews™ in Eukaryotic Gene Expression
IF: 1.841 5-Year IF: 1.927 SJR: 0.627 SNIP: 0.516 CiteScore™: 1.96

ISSN Print: 1045-4403
ISSN Online: 2162-6502

Critical Reviews™ in Eukaryotic Gene Expression

DOI: 10.1615/CritRevEukaryotGeneExpr.v9.i1.50
pages 59-88

Contributions of Gla and EGF-Like Domains to the Function of Vitamin K-Dependent Coagulation Factors

Johan Stenflo
Department of Clinical Chemistry, University of Lund, University Hospital, Malmo, SE-205 02 Malmo, Sweden

ABSTRACT

Blood coagulation is a response to vascular injury leading to the activation of platelets and coagulation factors with the ultimate formation of a fibrin plug. Several coagulation factors are zymogens of serine proteases that require vitamin K for normal biosynthesis. The active forms of these proteases and their cofactors form membrane-bound macromolecular complexes. In the final step prothrombin is activated to thrombin by active factor X in complex with its cofactor, factor V. Thrombin then cleaves designated peptide bonds in fibrinogen, resulting in the formation of fibrin monomers that polymerize to insoluble fibrin strands. This process is regulated by an anticoagulant counterpart, the so-called protein C anticoagulant system. Balance between the two systems is crucial to avoid bleeding on the one hand and thrombosis on the other. The coagulation and anticoagulation proteases, factors VII, IX, and X, and protein C, have a common domain structure with an N-terminal γ-carboxyglutamic acid (Gla)-containing domain that is followed by two domains that are homologous to the epidermal growth factor (EGF), whereas the C-terminal half of each protein is occupied by a trypsin-like serine protease domain. Prothrombin also has an N-terminal Gla domain and a C-terminal serine protease domain, but they are separated by two so-called kringle domains rather than EGF-like domains. Finally, the vitamin K-dependent cofactor protein S has one domain with thrombin-sensitive bonds and four EGF-like domains in tandem between the Gla domain and a C-terminal domain that is homologous to plasma steroid hormone-binding proteins. The N-terminal noncatalytic Gla and EGF-like domains that provide the coagulation serine proteases with unique properties, such as affinity for certain biological membranes, and also mediate protein-protein interactions, are the subject of this review.


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