Document Detail


Heparin-dependent modification of the reactive center arginine of antithrombin and consequent increase in heparin binding affinity.
MedLine Citation:
PMID:  9242619     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Antithrombin, the principal plasma inhibitor of coagulation proteinases, circulates in a form with low inhibitory activity due to partial insertion of its reactive site loop into the A-beta-sheet of the molecule. Recent crystallographic structures reveal the structural changes that occur when antithrombin is activated by the heparin pentasaccharide, with the exception of the final changes, which take place at the reactive center itself. Here we show that the side chain of the P1 Arg of alpha-antithrombin is only accessible to modification by the enzyme peptidylarginine deiminase on addition of the heparin pentasaccharide, thereby inactivating the inhibitor, whereas the natural P1 His variant, antithrombin Glasgow, is unaffected, indicating that only the P1 Arg becomes accessible. Furthermore, the deimination of P1 Arg converts antithrombin to a form with 4-fold higher affinity for the heparin pentasaccharide, similar to the affinity found for the P1 His variant, due to a lowered dissociation rate constant for the antithrombin-pentasaccharide complex. The results support the proposal that antithrombin circulates in a constrained conformation, which when released, in this study by perturbation of the bonding of P1 Arg to the body of the molecule, allows the reactive site loop to take up the active inhibitory conformation with exposure of the P1 Arg.
Authors:
R N Pike; J Potempa; R Skinner; H L Fitton; W T McGraw; J Travis; M Owen; L Jin; R W Carrell
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  272     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1997 Aug 
Date Detail:
Created Date:  1997-09-05     Completed Date:  1997-09-05     Revised Date:  2009-09-29    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  19652-5     Citation Subset:  IM    
Affiliation:
Department of Haematology, University of Cambridge, MRC Centre, Hills Road, Cambridge CB2 2QH, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Antithrombin III / metabolism*
Arginine / metabolism*
Binding Sites
Heparin / metabolism*
Humans
Hydrolases / metabolism
Isoelectric Focusing
Models, Molecular
Oligosaccharides / metabolism*
Protein Conformation
Grant Support
ID/Acronym/Agency:
HL 26148/HL/NHLBI NIH HHS; //Wellcome Trust
Chemical
Reg. No./Substance:
0/Oligosaccharides; 115299-92-8/antithrombin III Glasgow; 74-79-3/Arginine; 88096-19-9/IC 831423; 9000-94-6/Antithrombin III; 9005-49-6/Heparin; EC 3.-/Hydrolases; EC 3.5.3.15/peptidylarginine deiminase type IV; EC 3.5.3.15/protein-arginine deiminase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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