The heavy chain of factor Va is necessary for efficient activation of prothrombin but the molecular basis for this is not known. Several groups have shown independently that the truncation of the heavy chain from the C-terminus by at least 51 residues substantially reduces the efficiency of prothrombin activation. One group has concluded that the hirudin- like sequence DYDYQ in the C-terminus of the heavy chain is important for prothrombin activation and it determines the pathway of prothrombin activation. Another group, however, concluded that this sequence is irrelevant to prothrombin activation. They did find, however, that mutants lacking the ten residues C-terminal to the DYDYQ sequence are deficient in prethrombin-1 activation. Prethrombin-1 activation kinetics are much slower than prothrombin activation kinetics with human prothrombinase because of the lack of membrane binding. The precise role of the heavy chain of factor Va in prothrombin activation is yet to be determined.
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Substantial difference exists between human and bovine factor Va in the activation of prethrombin-1 by prothrombinase. Differences in kinetics can be attributed to the differences in sequences of the C- terminus of heavy chain, where the human and bovine differ substantially in their respective pI values, despite high sequence homology between the conserved domains of the heavy chain. The difference in prethrombin-1 activation is specifically due to retardation of Arg320 cleavage of prethrombin-1 with human Va, but not with bovine Va. These studies suggest that the residues C- terminal to the DYDYQ sequence influence cleavage at Arg320 in prethrombin-1 and may do so in prothrombin.
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