Role of the residues of the 39-loop in determining the substrate and inhibitor specificity of factor IXa.

The Journal of Biological Chemistry
Likui YangAlireza R Rezaie

Abstract

The activation of antithrombin (AT) by heparin facilitates the exosite-dependent interaction of the serpin with factors IXa (FIXa) and Xa (FXa), thereby improving the rate of reactions by 300- to 500-fold. Relative to FXa, AT inhibits FIXa with approximately 40-fold slower rate constant. Structural data suggest that differences in the residues of the 39-loop (residues 31-41) may partly be responsible for the differential reactivity of the two proteases with AT. This loop is highly acidic in FXa, containing three Glu residues at positions 36, 37, and 39. By contrast, the loop is shorter by one residue in FIXa (residue 37 is missing), and it contains a Lys and an Asp at positions 36 and 39, respectively. To determine whether differences in the residues of this loop contribute to the slower reactivity of FIXa with AT, we prepared an FIXa/FXa chimera in which the 39-loop of the protease was replaced with the corresponding loop of FXa. The chimeric mutant cleaved a FIXa-specific chromogenic substrate with normal catalytic efficiency, however, the mutant exhibited approximately 5-fold enhanced reactivity with AT specifically in the absence of the cofactor, heparin. Further studies revealed that the FIXa mutant activates factor X with...Continue Reading

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Citations

Mar 14, 2012·Biochemistry·Chandrashekhara ManithodyAlireza R Rezaie
Jul 24, 2014·Journal of Biomolecular Structure & Dynamics·Qudsia RashidMohamad Aman Jairajpuri
Aug 11, 2016·PloS One·Casey J KrusemarkPehr B Harbury
Mar 27, 2013·The Journal of Biological Chemistry·Likui Yang, Alireza R Rezaie
Dec 17, 2015·Pharmacological Reviews·Barbara MulloyClive P Page

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