Reference : Basic residues of human group IIA phospholipase A2 are important for binding to facto...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/20403
Basic residues of human group IIA phospholipase A2 are important for binding to factor Xa and prothrombinase inhibition comparison with other mammalian secreted phospholipases A2.
English
Mounier, C. M. [> > > >]
Luchetta, P. [> > > >]
Lecut, Christelle mailto [Institut Pasteur (Paris, France) > Unité des Venins > > >]
Koduri, R. S. [> > > >]
Faure, G. [> > > >]
Lambeau, G. [> > > >]
Valentin, E. [> > > >]
Singer, A. [> > > >]
Ghomashchi, F. [> > > >]
Beguin, S. [> > > >]
Gelb, M. H. [> > > >]
Bon, C. [> >]
2000
European Journal of Biochemistry
Blackwell Science
267
16
4960-9
Yes (verified by ORBi)
0014-2956
1432-1033
Oxford
United Kingdom
[en] Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Base Sequence ; Bothrops ; Factor Xa/metabolism ; Group II Phospholipases A2 ; Humans ; Mammals ; Mice ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Phospholipases A/chemistry/metabolism ; Phospholipases A2 ; Phospholipids/metabolism ; Protein Conformation ; Rats ; Recombinant Proteins/chemistry/metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Surface Plasmon Resonance ; Thrombin/metabolism ; Thromboplastin/antagonists & inhibitors
[en] Human secreted group IIA phospholipase A2 (hGIIA) was reported to inhibit prothrombinase activity because of binding to factor Xa. This study further shows that hGIIA and its catalytically inactive H48Q mutant prolong the lag time of thrombin generation in human platelet-rich plasma with similar efficiency, indicating that hGIIA exerts an anticoagulant effect independently of phospholipid hydrolysis under ex vivo conditions. Charge reversal of basic residues on the interfacial binding surface (IBS) of hGIIA leads to decreased ability to inhibit prothrombinase activity, which correlates with a reduced affinity for factor Xa, as determined by surface plasmon resonance. Mutation of other surface-exposed basic residues, hydrophobic residues on the IBS, and His48, does not affect the ability of hGIIA to inhibit prothrombinase activity and bind to factor Xa. Other basic, but not neutral or acidic, mammalian secreted phospholipases A2 (sPLA2s) exert a phospholipid-independent inhibitory effect on prothrombinase activity, suggesting that these basic sPLA2s also bind to factor Xa. In conclusion, this study demonstrates that the anticoagulant effect of hGIIA is independent of phospholipid hydrolysis and is based on its interaction with factor Xa, leading to prothrombinase inhibition, even under ex vivo conditions. This study also shows that such an interaction involves basic residues located on the IBS of hGIIA, and suggests that other basic mammalian sPLA2s may also inhibit blood coagulation by a similar mechanism to that described for hGIIA.
http://hdl.handle.net/2268/20403

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