RNA aptamer to thrombin binds anion-binding exosite-2 and alters protease inhibition by heparin-binding serpins

We studied the RNA aptamer Toggle-25/thrombin interaction during inhibition by antithrombin (AT), heparin cofactor II (HCII) and protein C inhibitor (PCI). Thrombin inhibition was reduced 3-fold by Toggle-25 for AT and HCII, but it was slightly enhanced for PCI. In the presence of glycosaminoglycans...

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Bibliographic Details
Published in:FEBS letters 2004-06, Vol.568 (1), p.10-14
Main Authors: Jeter, Martha L, Ly, Linda V, Fortenberry, Yolanda M, Whinna, Herbert C, White, Rebekah R, Rusconi, Christopher P, Sullenger, Bruce A, Church, Frank C
Format: Article
Language:English
Subjects:
Anions
Antithrombins - metabolism
AT, antithrombin
Base Sequence
Binding Sites
exosite-1 and -2, anion-binding exosite-1 and anion-binding exosite-2
Glycosaminoglycans - metabolism
HCII, heparin cofactor II
Heparin
Heparin - metabolism
Heparin Cofactor II - metabolism
Humans
Models, Molecular
PCI, protein C inhibitor
Protein C Inhibitor - metabolism
RNA - chemistry
RNA - metabolism
RNA aptamer
Serpin
Serpin, serine protease inhibitor
Thrombin
Thrombin - metabolism
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Summary:We studied the RNA aptamer Toggle-25/thrombin interaction during inhibition by antithrombin (AT), heparin cofactor II (HCII) and protein C inhibitor (PCI). Thrombin inhibition was reduced 3-fold by Toggle-25 for AT and HCII, but it was slightly enhanced for PCI. In the presence of glycosaminoglycans, AT and PCI had significantly reduced thrombin inhibition with Toggle-25, but it was only reduced 3-fold for HCII. This suggested that the primary effect of aptamer binding was through the heparin-binding site of thrombin, anion-binding exosite-2 (exosite-2). We localized the Toggle-25 binding site to Arg 98, Glu 169, Lys 174, Asp 175, Arg 245, and Lys 248 of exosite-2. We conclude that a RNA aptamer to thrombin exosite-2 might provide an effective clinical reagent to control heparin's anticoagulant action.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2004.04.087