NDLI: An Anticoagulant RNA Aptamer That Inhibits Proteinase-Cofactor Interactions within Prothrombinase*

Content Provider	PubMed Central
Author	Buddai, Sai K. Layzer, Juliana M. Lu, Genmin Rusconi, Christopher P. Sullenger, Bruce A. Monroe, Dougald M. Krishnaswamy, Sriram
Abstract	The interaction of factor Xa with factor Va on membranes to form prothrombinase profoundly increases the rate of the proteolytic conversion of prothrombin to thrombin. We present the characterization of an RNA aptamer (RNA11F7t) selected from a combinatorial library based on its ability to bind factor Xa. We show that RNA11F7t inhibits thrombin formation catalyzed by prothrombinase without obscuring the active site of Xa within the enzyme complex. Selective inhibition of protein substrate cleavage arises from the ability of the aptamer to bind to factor Xa and exclude interactions between the proteinase and cofactor within prothrombinase. Competition for enzyme complex assembly results from the binding of RNA11F7t to factor Xa with nanomolar affinity in a Ca2+-dependent interaction. RNA11F7t binds equivalently to the zymogen factor X as well as derivatives lacking γ-carboxyglutamic acid residues. We suggest that the ability of RNA11F7t to compete for the Xa-Va interaction with surprisingly high affinity likely reflects a significant contribution from its ability to indirectly impact regions of Xa that participate in the proteinase-cofactor interaction. Thus, despite the complexity of the macromolecular interactions that underlie the assembly of prothrombinase, efficient inhibition of enzyme complex assembly and thrombin formation can be achieved by tight binding ligands that target factor Xa in a discrete manner.
Related Links	http://dx.doi.org/10.1074/jbc.m109.049833
Ending Page	5223
Page Count	12
Starting Page	5212
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	8
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-02-19
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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An Anticoagulant RNA Aptamer That Inhibits Proteinase-Cofactor Interactions within Prothrombinase

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