L.H.Kristensen
et al.
(2016).
Releasing the brakes in coagulation Factor IXa by co-operative maturation of the substrate-binding site.
Biochem J,
473,
2395-2411.
PubMed id: 27208168
DOI: 10.1042/BCJ20160336
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
Ile(212)-Ile(213) motif unique to Factor IXa and a flexibility of the 170-loop
that is further dependent on the conformation in the Cys(168)-Cys(182) disulfide
bond. Ultimately, the network consists of compensatory brakes (Val(16) and
Ile(213)) and accelerators (Tyr(99) and Phe(174)) that together allow for a
subtle fine-tuning of enzymatic activity.
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