Coagulation Factor IX is positioned at the merging point of the intrinsic and extrinsic blood coagulation cascades. Factor IXa (activated Factor IX) serves as the trigger for amplification of coagulation through formation of the so-called Xase complex, which is a ternary complex of Factor IXa, its substrate Factor X and the cofactor Factor VIIIa on the surface of activated platelets. Within the Xase complex the substrate turnover by Factor IXa is enhanced 200000-fold; however, the mechanistic and structural basis for this dramatic enhancement remains only partly understood. A multifaceted approach using enzymatic, biophysical and crystallographic methods to evaluate a key set of activity-enhanced Factor IXa variants has demonstrated a delicately balanced bidirectional network. Essential molecular interactions across multiple regions of the Factor IXa molecule co-operate in the maturation of the active site. This maturation is specifically facilitated by long-range communication through the Ile212–Ile213 motif unique to Factor IXa and a flexibility of the 170-loop that is further dependent on the conformation in the Cys168–Cys182 disulfide bond. Ultimately, the network consists of compensatory brakes (Val16 and Ile213) and accelerators (Tyr99 and Phe174) that together allow for a subtle fine-tuning of enzymatic activity.
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Research Article|
July 28 2016
Releasing the brakes in coagulation Factor IXa by co-operative maturation of the substrate-binding site
Line Hyltoft Kristensen;
Line Hyltoft Kristensen
1
*Haemophilia Biochemistry, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark
†Structural Biology Group, Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria
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Ole H. Olsen;
Ole H. Olsen
2
*Haemophilia Biochemistry, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark
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Grant E. Blouse;
*Haemophilia Biochemistry, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark
4Correspondence may be addressed to either of these authors (email geb@novonordisk.com or hans.Brandstetter@sbg.ac.at).
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Hans Brandstetter
Hans Brandstetter
4
†Structural Biology Group, Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria
4Correspondence may be addressed to either of these authors (email geb@novonordisk.com or hans.Brandstetter@sbg.ac.at).
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Publisher: Portland Press Ltd
Received:
April 13 2016
Revision Received:
April 25 2016
Accepted:
May 19 2016
Accepted Manuscript online:
May 19 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (15): 2395–2411.
Article history
Received:
April 13 2016
Revision Received:
April 25 2016
Accepted:
May 19 2016
Accepted Manuscript online:
May 19 2016
Citation
Line Hyltoft Kristensen, Ole H. Olsen, Grant E. Blouse, Hans Brandstetter; Releasing the brakes in coagulation Factor IXa by co-operative maturation of the substrate-binding site. Biochem J 1 August 2016; 473 (15): 2395–2411. doi: https://doi.org/10.1042/BCJ20160336
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