Activation of coagulation factor IX is a pivotal reaction in the formation and maintenance of a fibrin clot. Factor IX is activated by two structurally unrelated enzymes; factor XIa of the intrinsic coagulation cascade and the extrinsic cascade complex of factor VIIa and tissue factor. Factor IX is activated by cleavage of two internal peptide bonds, resulting in the release of an activation peptide. Both factor VIIa/tissue factor and factor XIa make the same cleavages in factor IX, but appear to do so by different mechanisms that involve different rate limiting steps. While the factor VIIa/tissue factor complex has one catalytic domain per complex, factor XIa is a unique homodimer with up to two active serine protease domains per molecule. Factor XIa appears to cleave both scissile bonds in factor IX without releasing an intermediate, while factor VIIa/tissue factor releases a singly cleaved intermediate. This observation has led many investigators to postulate that factor XIa, acting via a processive mechanism, can make both cleavages in factor IX simultaneously without generating any singly cleaved intermediate forms of factor IX.
Based on observations suggesting that factor XIa contributes to obstructive (thrombotic) clot formation to a greater degree than to normal coagulation at a wound site, there is increased interest in the mechanism by which factor XIa is formed, and by which factor XIa cleaves factor IX. Regulation of clotting factors follows their form, and most pro-coagulant molecules are directed to assemble on injured surfaces by common accessory domains. Factor XIa is unique in this regard in that it does not appear to require either co-factors or damaged surfaces for its activation or for cleavage of factor IX once activated. The relationship between the unique structural features of factor XIa and its unusual mode of action is poorly understood.
Here we present evidence that factor XIa with only one active subunit per molecule can be formed, is produced in plasma, and can activate factor IX without intermediate accumulation. Our data, along with the recently solved structure of the zymogen precursor of factor XIa, factor XI, suggests that the structure of factor XIa allows its subunits to act independently of each other, a behavior that has not been described previously for a serine protease.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03272009-134726 |
| Date | 09 April 2009 |
| Creators | Smith, Stephen Bradford |
| Contributors | Paul Bock, Ingrid Verhamme, Richard Hoover, Martin Egli, Munirathinam Sundaramoorthy |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-03272009-134726/ |
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