F ibrin degradation products (FDPs) formation with subsequent release into bloodstream is a result of fibrinolytic system action. The main fibrinolytic enzyme plasmin is generated from inert precursor plasminogen by either tissuetype plasminogen activator (t-PA) or urokinase-type plasminogen activator [1]. According to molecular mechanism of fibrinolysis, plasminogen and its tissue-type activator from plasma bind to fibrin, and plasminogen activator converts proenzyme into plasmin. Fibrin formed during clotting process, as fibrinogen polyme rization result is a high-avid substrate and at the same time a stimulator for plasmin. Plasminogen/t-PA binding sites in D-regions subsequently Аα 148-160 and γ 312-324 are hidden in fibrinogen molecule and exposed under polymerization and fibrin clot formation [2]. The conversion provides increase of plasminogen and its activator local concentration, change of their conformation and orientation, resul ted in fast proenzyme activation and fibrin cleavage by newly formed plasmin.First step of degradation of individual fibrin(ogen) molecule by plasmin is αC-domains removal and X-fragment formation. Than plasmin cleaves one of the coiled-coil connector and removes onе of D-domains forming Y-fragment. The last stage is core fragments D and E formation. The lysis of polymeric fibrin cross-linked by FXIIIa leads to formation of intermediate high-molecular weight products that are the protofibril parts, for example DX n D, DXY, YY, DY. In vivo these molecules can form supramolecular complexes due to the noncovalent DDE-interaction [3] and contain different number of DDE-blocks. In this work the complex of soluble high molecular weight fibrin degradation products are called hmFDPs. During further degradation, these products are hydrolyzed to DDE-complexes (two covalently bound D-domains noncovalently associated with fragment E 1 or E 2 ) and then to core fragments DD and E 3 . Fibrin degradation products get in wide range of biological processes and affect all stages of hemostasis [4]. Soluble products of fibrin degradation stimulate t-PA-induced fibrinogen proteolysis in blood plasma [5]. FDPs activate inflammatory and/or structural cells and regulate smooth muscle cell migration [6]. Like fibrin, DDE-complex can bind plasminogen and its activator [7]. DD-fragment, a biomarker for hyperfibrinolytic disorders such as disseminated intravascular coagulation (DIC), attenuates the fibrin
The interaction of the fifth kringle of Glu-plasminogen with fibrin triggers activation and initiation of fibrinolysis, yet the site on fibrin that binds kringle 5 remains unknown. The aim of our work was to determine an amino acid sequence in the D-fragment of fibrin(ogen) molecule, which is complementary to the lysine-binding site (LBS) in kringle 5. We studied the interaction between kringle 5 of plasminogen with polypeptide chains of the D-fragments of fibrin and cyanogen bromide fragments FCB-2 and t-NDSK and showed that kringle 5 bound specifically to α-and γ-chains of the D-fragment and the α-chain of FCB-2. Tryptic peptides of D-fragment α-chain were obtained, separated by their ability to bind with the immobilized kringle 5, and then all studied peptides were characterized by MALDI-TOF analysis. The critical amino acid residues of the α-chain of D-fragment, which provide its interaction with kringle 5, turned out to be α171Arg and/or α176Lys. The binding site of Glu-plasminogen complementary to the LBS of kringle 5 is located within Аα168Ala−183Lys, a sequence in a weakly structured loop between two supercoils in the α-chain of the Dfragment of the fibrin(ogen) molecule. K e y w o r d s: plasminogen, kringle 5, fibrin(ogen), binding site, α-chain of fibrin D-fragment, fibrinolysis.
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