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| Content Provider | Journal of Biological Chemistry (JBC) |
|---|---|
| Author | Regan, Lisa M. Fay, Philip J. |
| Abstract | Thrombin-catalyzed activation of heterodimeric factor VIII occurs by limited proteolysis, yielding subunits A1 and A2 derived from the heavy chain (HC) and A3-C1-C2 derived from the light chain (LC). The roles of these cleavages in the function of procoagulant activity are poorly understood. To determine whether LC cleavage contributes to the potentiation of factor VIII activity, factor VIII heterodimers were reconstituted from native HC and either thrombin-cleaved LC (A3-C1-C2) or intact LC and purified by Mono S chromatography. The reconstituted factor VIII form containing the A3-C1-C2 subunit had a specific activity (2 units/μg) that was 3-fold greater than that of the reconstituted factor VIII form containing native LC (0.6 units/μg). Factor Xa generation assays using the hybrid heterodimer showed an initial rate that was unaffected by the presence of von Willebrand factor and a reduced lag time when compared with the native heterodimer. The A1/A3-C1-C2 dimer was dissociated by chelation, and the purified A1 subunit was reacted with either the A3-C1-C2 subunit or the LC in the presence of Mnto reconstitute the dimer. Factor VIIIa heterotrimers were reconstituted from either A1/A3-C1-C2 or A1/LC plus the A2 subunit. The authentic factor VIIIa heterotrimer (A1/A3-C1-C2/A2) had 3-fold greater activity than the form containing the LC. However, upon reaction with thrombin, the activity of the latter form was increased to that of the factor VIIIa form containing native subunits. The incremental increase in fluorescence anisotropy of fluorescein-Phe-Phe-Arg chloromethyl ketone-modified factor IXa was markedly greater in the presence of HC/A3-C1-C2 (Δ r = 0.037) compared with HC/LC (Δ r = 0.011) and approached the value obtained with factor VIIIa (Δ r = 0.051). These results suggest that cleavage of factor VIII LC directly contributes to the potentiation of coagulant activity by modulating the conformation of the factor IXa active site. |
| Related Links | http://www.jbc.org/content/270/15/8546.abstract |
| Ending Page | 8552 |
| Starting Page | 8546 |
| Page Count | 7 |
| File Format | HTM / HTML PDF |
| ISSN | 00219258 |
| Journal | Journal of Biological Chemistry (JBC) |
| Issue Number | 15 |
| Volume Number | 270 |
| DOI | 10.1074/jbc.270.15.8546 |
| e-ISSN | 1083351X |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology |
| Publisher Date | 1995-04-14 |
| Access Restriction | Open |
| Subject Keyword | Protein Chemistry and Structure |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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