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Human protein S cleavage and inactivation by coagulation factor Xa
1Department of Biochemistry, University of Vermont College of Medicine, Burlington, Vermont 05405-0068, USA. glong@zoo.uvm.edu
The Journal of Biological Chemistry
|June 13, 1998
Summary
Human factor Xa cleaves anticoagulant protein S, inactivating its anticoagulant properties. This cleavage, requiring specific conditions, may enhance factor Xa's procoagulant effect during clot formation.
Area of Science:
- Biochemistry
- Hematology
- Molecular Biology
Background:
- Protein S is a crucial anticoagulant protein.
- Factor Xa is a key enzyme in the coagulation cascade.
Purpose of the Study:
- To investigate the specific cleavage site of protein S by human factor Xa.
- To determine the functional consequences of factor Xa-mediated cleavage of protein S.
Main Methods:
- Amino-terminal amino acid sequencing to identify cleavage site.
- Clot inhibition assays using specific factor Xa inhibitors (tick-anticoagulant-peptide, D-Glu-Gly-Arg-chloromethyl ketone).
- Assays measuring anticoagulant activity in the presence of phospholipid, Ca2+, and factor Va.
Main Results:
- Factor Xa cleaves protein S at Arg60, a distinct site from alpha-thrombin.
- Cleavage is specific to factor Xa and requires phospholipid and Ca2+.
- Factor Xa-cleaved protein S loses all anticoagulant activity, independent of membrane binding ability.
Conclusions:
- Factor Xa directly inactivates protein S, diminishing its anticoagulant function.
- This inactivation mechanism may contribute to factor Xa's procoagulant role.
- Cleavage by factor Xa represents a novel regulatory pathway in hemostasis.