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Conformational Changes upon Conversion of Fibrinogen into Fibrin
Author(s) -
MEDVED LEONID,
TSURUPA GALINA,
YAKOVLEV SERGEI
Publication year - 2001
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2001.tb03505.x
Subject(s) - fibrinogen , fibrin , chemistry , epitope , fibrinolysis , plasminogen activator , biophysics , alpha (finance) , conformational change , stereochemistry , biochemistry , antibody , immunology , biology , medicine , construct validity , nursing , psychiatry , patient satisfaction , endocrinology
A bstract : Conformational changes upon conversion of fibrinogen to fibrin result in the exposure of multiple binding sites that provide its interaction with various proteins and cells and, thus, its participation in a number of physiological and pathological processes. Here we focus on conformational changes in the fibrinogen D regions (domains) and αC‐domains that are directly involved in intermolecular interactions upon fibrin assembly. According to the current view, two αC‐domains that interact intramolecularly in fibrinogen undergo an intra‐ to intermolecular switch to form αC‐polymers in fibrin. The availability of recombinant fragments that correspond to the αC‐domain made it possible to further clarify this mechanism and to reveal novel cryptic sites in this domain for plasminogen and its activator tPA, whose exposure may play an important role in the regulation of fibrinolysis. To elucidate the mechanism of exposure of cryptic sites in the D regions, we tested the accessibility of their fibrin specific epitopes (Aα148–160 and γ312–324) that are also involved in binding of plasminogen and tPA, in several fragments derived from fibrinogen (fragment D), and crosslinked fibrin (fragment D‐D and its non‐covalent complex with the E 1 fragment, D‐D:E 1 ). Neither D nor D‐D bound tPA, plasminogen, or anti‐Aα148–160 and anti‐γ312–324 monoclonal antibodies. At the same time both epitopes became accessible in the D‐D:E 1 complex. Melting of D and D‐D revealed that their domains have the same stability while in the D‐D:E 1 complex they became more stable. These results indicate that upon fibrin assembly, driven primarily by the interaction between complementary binding sites of the E and two D regions, the latter undergo conformational changes that cause the exposure of their cryptic sites. They also suggest that the fibrin specific conformation of the D regions is preserved in the D‐D:E 1 complex.