Fibrin-mediated plasminogen activation

Fibrin, but not fibrinogen, enhances the rate of activation of plasminogen by tissue type plasminogen activator (t-PA). Studies with enzymatic and chemical fragments of fibrinogen showed that several sites in fibrinogen are involved in this rate enhancement; these are, Aα148-160 (located in CNBr fragment FCB-2), and FCB-5 (a CNBr fragment comprising γ312-324), and recently discovered sites in the fibrinogen αC domains. All these sites are buried in fibrinogen, but exposed in fibrin and some fibrinogen fragments. For the first two of these, located in the D-domains, this was shown by the fact that monoclonal antibodies against Aα148-160 and γ312-324 bind to fibrin and rate enhancing fibrin(ogen) fragments, but not to fibrinogen. Direct binding studies indicate that at physiological concentrations plasminogen binds to FCB-2, and t-PA to FCB-5. More detailed studies have demonstrated the importance of residues Aα-157 and Aα-152, and that the minimum stretch with rate enhancing properties is Aα154-159. The sites in the αC domains await further identification. With the recently reported three-dimensional structure of fragments D and D-dimer it is now possible to explain these findings at the molecular level. Molecular calculations and experimental data show that the site Aα148-160 in fibrinogen is covered among others by a part of the Aα chain (Aα166-195) that forms an α-helix, and by a globular domain formed by the β-chain. On fibrin formation, the last two may move away, and give access to Aα148-160. It is conceivable that in the αC domain sites are involved in the early phases of fibrinolysis. The site Aα148-160 and that in FCB-5 may be more important at later stages. It is also clear that fibrin polymerization is important. This polymerization has probably several effects: exposure of the rate enhancing sites; mutual positioning of the t-PA and plasminogen binding sites; a concentrating effect of t-PA and plasminogen on the fibrin surface; effects on the kinetic properties of t-PA and plasminogen. These effects together explain the rate enhancement.
Chemicals/CAS: Fibrin, 9001-31-4; Fibrinogen, 9001-32-5; Plasminogen, 9001-91-6; Tissue Plasminogen Activator, EC 3.4.21.68