Dahlbäck B
Department of Clinical Chemistry, University of Lund, Malmö General Hospital, Sweden.
Scand J Clin Lab Invest Suppl. 1988;191:47-61. doi: 10.1080/00365518809168293.
Blood coagulation factor V, the labile factor, is an important cofactor in the activation of prothrombin. Approximately 10 years ago, the first purification procedures for undegraded factor V from bovine and human plasma were reported. This was the starting point for a new area in the research on factor V structure-function relationships. In parallel to this, the structure of the even more labile anti-hemophilic factor (factor VIII) has been elucidated and the two proteins are found to be very similar in structure and in function. In this mini-review, I will focus on work performed in our laboratory, which has led forward to the proposal of a new structural model for factor V. It is based on results obtained with several different techniques, including protein chemistry, DNA technology and high resolution electron microscopy. In plasma, factor V circulates as a single chain, high molecular weight protein. During coagulation a limited number of peptide bonds are cleaved in the factor V molecule by thrombin. This leads to a great increase in biological activity. The active Va species is composed of a noncovalent complex between the N- and C-terminal fragments, whereas the activation fragments correspond to the carbohydrate-rich central portion of the molecule. The activity of factor Va is regulated through the selective degradation of the N-terminal heavy chain fragment by activated protein C. Purified human and bovine factor V was examined by high resolution transmission electron microscopy. Factor V was found to be composed of four major domains, three similar sized globular structures (diameter approx. 80 A) are linked via thin spacers to a larger central domain (diameter approx. 140 A). Activation with thrombin results in a reorganization of the molecule. The thrombin cleavage sites are positioned in the spacers between the different domains and two of the peripheral domains combine to form the active Va species. The new factor V model suggests that a unique and dramatic molecular reorganization occurs during the activation of factor V by thrombin and indicates that the low biological activity of single chain factor V is due to the physical separation of the N- and C-terminal domains by the large central region. Full biological activity can only be expressed after limited proteolysis by thrombin, when the two initially separated domains are free to combine to form the active factor Va molecule.
