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Tissue factor activates allosteric networks in factor VII a through structural and dynamic changes
Author(s) -
Madsen J. J.,
Persson E.,
Olsen O. H.
Publication year - 2015
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12791
Subject(s) - allosteric regulation , tissue factor , chemistry , catalytic triad , active site , biophysics , protease , biochemistry , enzyme , biology , psychology , psychiatry , coagulation
Summary Background Tissue factor ( TF ) promotes colocalization of enzyme (factor VII a) and substrate ( FX or FIX ), and stabilizes the active conformation of FVII a. Details on how TF induces structural and dynamic changes in the catalytic domain of FVII a to enhance its efficiency remain elusive. Objective To elucidate the activation of allosteric networks in the catalytic domain of the FVII a protease it is when bound to TF . Methods Long‐timescale molecular dynamics simulations of FVII a, free and in complex with TF , were executed and analyzed by dynamic network analysis. Results Allosteric paths of correlated motion from the TF contact point, Met306, in FVII a to the active site triad can be described and quantified. In particular, the shortest paths from Met306 to Ser344 and His193 are 16% and 8% longer in free FVII a than in TF – FVII a, and they encompass previously undiscovered residue–residue interactions that are not likely to be inferred from mutagenesis studies. Furthermore, paths from Met306 to Ile153 (N‐terminus) and Trp364, both representing hallmark residues of allostery, are 7% and 37% longer, respectively, in free FVII a. Thus, there is significantly weaker coupling between the TF contact point and key residues in the catalytic domain of FVII a, causing the active site triad to disintegrate in the simulation when TF is not present. Conclusions These findings complement our current understanding of how the protease FVII a is stimulated by TF . We demonstrate allosteric networks in the catalytic domain that are activated by TF and help to make FVII a an efficient catalyst of FIX and FX activation.