S. Yakovlev et al., Conversion of fibrinogen to fibrin: Mechanism of exposure of tPA- and plasminogen-binding sites, BIOCHEM, 39(51), 2000, pp. 15730-15741
Conversion of fibrinogen into fibrin results in the exposure of cryptic int
eraction sites and modulation of various activities. To elucidate the mecha
nism of this exposure, we tested the accessibility of the A alpha 148-160 a
nd gamma 312-324 fibrin-specific epitopes that are involved in binding of p
lasminogen and its activator tPA, in several fragments derived from fibrino
gen (fragment D and its subfragments) and fibrin (cross-linked D-D fragment
and its noncovalent complex with the E-1 fragment, D-D.E-1). Neither D nor
D-D bound tPA, plasminogen, or anti-A alpha 148-160 and anti-gamma 312-324
monoclonal antibodies, indicating that their fibrin-specific epitopes were
inaccessible. The A alpha 148-160 epitope became exposed only upon proteol
ytic removal of the beta- and gamma -modules from D. At the same time, both
epitopes were accessible in the D-D.E-1 complex, indicating that the DD.E
interaction resulted in their exposure. This exposure was reversible since
the dissociation of the D-D.E-1 complex made the sites unavailable, while r
econstitution of the complex made them exposed. The results indicate that u
pon fibrin assembly, driven primarily by the interaction between complement
ary sites of the D and E regions, the D regions undergo conformational chan
ges that cause the exposure of their plasminogen- and tPA-binding sites. Th
ese changes may be involved in the regulation of fibrin assembly and fibrin
olysis.