Thrombin, produced by the prothrombinase complex, in addition to having a potent stimulatory effect on platelets (see earlier), converts fibrinogen to fibrin. Fibrinogen(factor I, 340 kDa) is an abundant (3 mg/mL) soluble plasma glycoprotein that consists of a dimer of three polypeptide chains, (Aα, Bβ, γ)2 , that is covalently linked by 29 disulfide bonds. The Bβ and γ chains contain asparagine-linked complex oligosaccharides. All three chains are synthesized in the liver; the three genes encoding these proteins are on the same chromosome where their expression is coordinately regulated in humans. The amino-terminal regions of the six chains are held in close proximity by a number of disulfide bonds (a subset is shown in Figure 1), while the carboxyl-terminal regions are spread apart. Thus, the fibrinogen molecule has a trinodular, elongated structure with a central E domain that is linked to lateral D domains via coiled coil regions (Figure 1 and Figure 2A). The N-terminal A and B portions of the Aα and Bβ chains are termed fibrino peptide A (FPA) and fibrinopeptide B (FPB), respectively; these domains are highly negatively charged as a result of an abundance of aspartate and glutamate residues. The negative charges contribute to the solubility of fibrinogen in plasma and importantly also serve to prevent aggregation by causing electrostatic repulsion between fibrinogen molecules.

Fig1. Diagrammatic representation of fibrinogen. (A)Fibrinogen is a dimeric molecule, with each half composed of three polypeptide chains: Aα, Bβ, and γ. Disulfide bonds join together the chains and the two halves of the molecule. (B) Fibrinogen forms a trinodular structure with a central E domain linked via coiled coil regions to two lateral D domains each of which contains a flexible Aα chain αC domain. The thrombin-cleaved regulatory peptides fibrinopeptide A (FPA) and fibrinopeptide B (FPB) reside within the E nodule as shown.

Fig2. Fibrin polymerization and degradation. (A)The formation of fibrin monomer via cleavage of fibrinopeptide A (FPA) and fibrinopeptide B (FPB) from fibrinogen by thrombin, the spontaneous polymerization of fibrin monomers to dimers and higher oligomers, followed by the stabilization of fibrin oligomers by factor XIIIa-mediated covalent cross-linking of adjacent fibrin monomers. Finally (bottom) is illustrated the degradation of fibrin polymers into soluble degradation products by plasmin digestion, which leads to clot dissolution. (B) Throm bin cleavage site of the Aα and Bβ chains of fibrinogen to yield FPA/FPB (left; green) and the α and β chains of fibrin monomer (right; black). (C) Schematic of factor XIIIa (transglutaminase)-mediated cross-linking of fibrin molecules.

Thrombin (34 kDa), the serine protease formed by the prothrombinase complex, hydrolyzes the four Arg-Gly bonds between the N-terminal fibrinopeptides and the α and β portions of the Aα and Bβ chains of fibrinogen (Figure 2A, B). The release of FPA and FPB by thrombin generates fibrin monomer, which has the subunit structure (α, β, γ)2 . Since FPA and FPB contain only 16 and 14 residues, respectively, the fibrin molecule retains 98% of the residues present in fibrinogen. The removal of the fibrinopeptides exposes binding sites within the E domain of fibrin monomers that specifically interact with complementary domains within the D domains of other fibrin monomers. In this way, fibrin monomers spontaneously polymerize in a half-staggered pattern to form long strands (protofibrils) (see Figure2A). Although insoluble, this initial fibrin clot is unstable, held together only by the noncovalent association of fibrin monomers.

In addition to converting fibrinogen to fibrin, thrombin also activates factor XIII to factor XIIIa. Factor XIIIa is a highly specific transglutaminase that covalently cross-links γ chains and, more slowly, α chains of fibrin molecules by forming peptide bonds between the amide groups of glutamine and the ε-amino groups of lysine residues (see Figure 2C). Such cross-linking yields a more stable fibrin clot with increased resistance to proteolysis. This fibrin mesh serves to stabilize the hemostatic plug or thrombus

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مواضيع ذات صلة

The Activity of Antithrombin, an Inhibitor of Thrombin, Is Increased by Heparin

Factor Xa Leads to Activation of Prothrombin to Thrombin

Most Transmembrane Proteins Have Membrane Spanning α Helices

Lipid Composition Is Different in the Exoplasmic and Cytosolic Leaflets

Lipid Composition Influences the Physical Properties of Membranes

The Intrinsic Pathway Also Leads to Activation of Factor X

The Extrinsic Pathway Leads to Activation of Factor X

Both Extrinsic & Intrinsic Coagulation Pathways Result in the Formation of Fibrin

Most Lipids and Many Proteins Are Laterally Mobile in Biomembranes

Biomembranes Contain Three Principal Classes of Lipids

Platelet Aggregation Requires Outside-In and Inside-Out Transmembrane Signaling

Phagocyte-Derived Proteases can Damage Healthy Cells