Each fibrinogen (fgn) molecule is comprised of two
sets of three polypeptide chains termed Aa,
Bb, and g
that are assembled in hepatocytes to form elongated 45 nm structures
consisting of 2 outer disulfide-bridged D domains, each connected by a
‘coiled-coil’ segment to its central disulfide-bridged E domain. The
domains in fgn contain several constitutive binding sites that participate in
fgn:fgn self-association, thrombin substrate binding to fgn that leads to
proteolytic conversion of fgn to fibrin (fbn), and to the subsequent
assembly of fbn units to form polymeric structures called ‘clots’. These clots
eventually undergo transglutaminase-catalyzed intermolecular covalent
‘crosslinking’ that is mediated either by circulating ‘unactivated’ plasma
factor XIII or by thrombin-activated factor XIIIa. A constitutive
binding site on fgn for factor XIII is located on a minor variant
and this chain also contains a ‘non-substrate’ thrombin-binding site that plays
a role in regulating thrombin generation in clotting blood (‘Antithrombin
I’). Initiation of fbn assembly occurs after thrombin-mediated cleavage of fibrinopeptide
A (FPA) to expose reactive polymerization sites (E
chains. These sites participate in complementary end-to-middle associations
between neighboring D and E domains (EA:D
and branched trimeric junctions that contribute to the formation of a
three-dimensional fbn network. The fbn polymerization process itself results in
exposure of D domain binding sites that enhance the fibrinolytic process [e.g.,
tissue plasminogen activator (tPA)]. Fibrils also undergo lateral
associations to form wider fibrils, fibers (i.e., many fibrils), and branches
that contribute to the integrity of the mature clot matrix. Somewhat later in
the proteolytic fgn to fbn conversion, thrombin-mediated cleavage of fibrinopeptide
B (FPB) leads to exposure of N-terminal b
chain sites (EB) that can
interact with receptors on vascular endothelial cells (VE-cadherin), or
with complementary polymerization sites in neighboring D domains (Db).
The (EB: Db) interaction
causes changes in conformation that create another D domain polymerization site
(bC). Other sites
located in fgn D domains bind to leucocyte integrin receptors (
presentation will attempt to correlate these biological events and interactions
with the overlapping roles that fgn and fbn play in blood clotting,
fibrinolysis, cellular and matrix interactions, inflammation, and wound
healing.
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