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Year : 2011  |  Volume : 2  |  Issue : 3  |  Page : 48  

Isozyme specific changes in antithrombin structure forms the basis of its improved heparin binding for anticoagulant activity


Protein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi-110025, India

Date of Web Publication26-May-2012

Correspondence Address:
Poonam Singh
Protein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi-110025
India
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Source of Support: None, Conflict of Interest: None


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How to cite this article:
Singh P, Singh K, Jairajpuri MA. Isozyme specific changes in antithrombin structure forms the basis of its improved heparin binding for anticoagulant activity. J Nat Sc Biol Med 2011;2, Suppl S1:48

How to cite this URL:
Singh P, Singh K, Jairajpuri MA. Isozyme specific changes in antithrombin structure forms the basis of its improved heparin binding for anticoagulant activity. J Nat Sc Biol Med [serial online] 2011 [cited 2020 Feb 24];2, Suppl S1:48. Available from: http://www.jnsbm.org/text.asp?2011/2/3/48/95790

Antithrombin III (ATIII) is the main inhibitor of the coagulation proteases like factor Xa and thrombin. Anticoagulant activity of ATIII is increased by several thousand folds when activated by vascular wall heparan sulfate proteoglycans (HSPGs) and pharmaceutical heparins. ATIII isoforms in human plasma, alpha-ATIII and beta-ATIII differ in the amount of glycosylation which is the basis of differences in their heparin binding affinity and function. Crystal structures and site directed mutagenesis studies have mapped the heparin binding site in ATIII, however the hydrogen bond switch and energetics of interaction during the course of heparin dependent conformational change in ATIII isoforms remains largely unclear. An overlap of alpha and beta structures of ATIII indicates that the differences between two isoforms are in or near the heparin binding site. Changes in beta like A-helix rearrangement, N-terminal movements and conformation shifting in the C and N terminal of the helix D are observed. Helix D region shows that the side-chains differ in alpha and beta ATIII forms. Pair-wise structural alignment of the output indicated an increase in helical content in the helix D towards the N-terminal end of beta ATIII. A Z-score of 64.5 and a RMSD value of 0.7 Ε indicated a close structural homology between the alpha and beta ATIII. We carried out the residue wise Accessible Surface Area (ASA) analysis of alpha and beta ATIII native states and the results indicated major differences in burial of residues from Ser 112 to Ser 116 towards the N-terminal end. This region is involved in the P-helix formation on account of heparin binding. A cavity analysis showed a progressively larger cavity formation during activation in the region just adjacent to the heparin binding site towards the C-terminal end. An analysis of heparin bound conformational states of ATIII using PEARLS software showed that in heparin bound intermediate state, Arg 47 and Arg 13 residues make hydrogen bonds with heparin but in the activated conformation Lys 11 and Lys 114 have more hydrogen bond interactions. In the protease bound-antithrombin-pentasaccharide complex Lys 114, Pro 12 and Lys 125 form important hydrogen bonding interactions. The results showed that A-helix and N-terminal end residues are more important in the initial interactions but D-helix is more important during the latter stage of conformational activation and during the process of protease inhibition. We hypothesize that during the process of conformational change after heparin binding beta form of antithrombin has low energy barrier to form D-helix extension toward N and C-terminal end as compared to alpha isoform. A hydrophobic cavity at the C-terminal of D-helix may play a critical role in the antithrombin activation mechanism.




 

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