fibrinogen/fibrin system for greater control of fibrin polymerization and degradation. In R21EB008463, we hypothesized that a fibrin knob fusion with thermo-responsive elastin-like peptide repeats will bind to fibrinogen polymerization pockets and prevent polymerization
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چکیده
Our long-term research goal is to understand and exploit the natural biochemical properties of the fibrinogen/fibrin system for greater control of fibrin polymerization and degradation. In R21EB008463, we hypothesized that a fibrin knob fusion with thermo-responsive elastin-like peptide repeats will bind to fibrinogen polymerization pockets and prevent polymerization in a temperature-dependent manner. We proposed 2 specific aims to address this hypothesis; SA1) design and express recombinant proteins displaying N-terminal fibrin polymerization knobs, and SA2) create recombinant knob-ELP fusion proteins and test their fibrinogenbinding/fibrin blocking activity.
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Synthetic peptide derivatives that bind to fibrinogen and prevent the polymerization of fibrin monomers.
A series of small peptides corresponding to the amino termini of the fibrin alpha- and beta-chains has been synthesized. The peptides glycyl-L-prolyl-L-arginyl-L-proline and glycyl-L-prolyl-L-arginylsarcosine are potent inhibitors of fibrin polymerization. Moreover, these peptides have a natural stability stemming from their inherent resistance to proteolysis because of the involvement of amino...
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Using laser tweezers, we measured for the first time the forces of individual knob-into-hole interactions underlying fibrin polymerization. Exposure of A-knobs in desA-fibrin or its fragment from the central part of the molecule (N-terminal disulphide knot, NDSK) resulted in strong interactions with fibrinogen or fragment D (containing only a- and b-holes), producing a binding strength of appro...
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The formation of a fibrin clot is initiated after the proteolytic cleavage of fibrinogen by thrombin. The enzyme removes fibrinopeptides A and B and generates fibrin monomer which spontaneously polymerizes. Polymerization appears to occur though the interaction of complementary binding sites on the NH2-terminal and COOH-terminal (Fragment D) regions of the molecule. A peptide has been isolated ...
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After vascular injury, a cascade of serine protease activations leads to the conversion of the soluble fibrinogen molecule into fibrin. The fibrin monomers then polymerize spontaneously and noncovalently to form a fibrin gel. The primary interaction of this polymerization reaction is between the newly exposed N-terminal Gly-Pro-Arg sequence of the a chain of one fibrin molecule and the C-termin...
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Fibrin polymerization is a necessary part of hemostasis but clots can obstruct blood vessels and cause heart attacks and strokes. The polymerization reactions are specific and controlled, involving strong knob-into-hole interactions to convert soluble fibrinogen into insoluble fibrin. It has long been assumed that clots and thrombi are stable structures until proteolytic digestion. On the contr...
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