Role of the gamma-carboxyglutamic acid domain of activated factor X in the presence of calcium during inhibition by antithrombin-heparin.

Asp 14 and 29 were enhanced without calcium; (ii) Gla-->Asp 16 and 26 were not enhanced by calcium; and (iii) Gla-->Asp 19 was essentially the same as wild-type recombinant FXa. These results support a theory that mutating individual Gla residues in FXa alters the calcium-induced conformational changes in the Gla region and affects the antithrombin-heparin inhibition reaction. -->
Grant Information: HL-04063 United States HL NHLBI NIH HHS; HL-06350 United States HL NHLBI NIH HHS; HL-08510 United States HL NHLBI NIH HHS; HL-32656 United States HL NHLBI NIH HHS; HL-48322 United States HL NHLBI NIH HHS
Substance Nomenclature: 0 (Antithrombins)
53445-96-8 (1-Carboxyglutamic Acid)
9005-49-6 (Heparin)
EC 3.4.21.6 (Factor Xa)
SY7Q814VUP (Calcium)
Entry Date(s): Date Created: 20040629 Date Completed: 20050302 Latest Revision: 20230829
Update Code: 20230830
DOI: 10.1111/j.1538-7836.2004.00796.x
PMID: 15219196
Autor: Whinna HC; Department of Pathology and Laboratory Medicine, Carolina Cardiovascular Biology Center, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. whinna@med.unc.edu, Lesesky EB, Monroe DM, High KA, Larson PJ, Church FC
Jazyk: angličtina
Zdroj: Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2004 Jul; Vol. 2 (7), pp. 1127-34.
DOI: 10.1111/j.1538-7836.2004.00796.x
Abstrakt: Background: Factor (F)Xa has 11 gamma-carboxylated glutamic acid (Gla) residues that are involved in calcium-dependent membrane binding. The serpin antithrombin (AT) is an important physiological regulator of FXa activity in an inhibition reaction that is enhanced by heparin. Recently, Rezaie showed that calcium further enhanced the heparin-catalyzed AT inhibition of FXa by promoting 'ternary complex' formation, and these results showed a role for the gamma-carboxyl-glutamate (Gla)-domain of FXa.
Objectives: In this study, we used recombinant FXa mutants to assess the role of individual Gla residues in augmenting or antagonizing the AT-heparin inhibition reaction in the presence of calcium.
Results and Conclusions: In the absence of heparin, AT inhibition of plasma and the recombinant FXas were essentially equivalent. Similar to plasma-derived FXa, calcium increased about 3-fold the inhibition rate of wild-type recombinant FXa by AT-heparin over that in the presence of EDTA. Interestingly, three different effects were found with the recombinant FXa Gla-mutants for AT-heparin inhibition: (i) Gla-->Asp 14 and 29 were enhanced without calcium; (ii) Gla-->Asp 16 and 26 were not enhanced by calcium; and (iii) Gla-->Asp 19 was essentially the same as wild-type recombinant FXa. These results support a theory that mutating individual Gla residues in FXa alters the calcium-induced conformational changes in the Gla region and affects the antithrombin-heparin inhibition reaction.
Databáze: MEDLINE
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