Fibrinogen/fibrin crosslinking

Many isopeptide bonds can be formed between the side chains of e-lysine (donor) and 7-glutamine (acceptor) residues (Fig. 8). The 7 chains of fibrinogen are crosslinked or ligated first, followed by the C-terminal a chains. In addition, other proteins—notably n2-antiplasmin, plasminogen activator inhibitor-2, and fibronectin—are also covalently ligated to fibrin by Factor XHIa (Greenberg et al, 2003). 

Skarja, G. A., Brash, J. L., Bishop, R, and Woodhouse, K. A. (1998). Protein and platelet interactions with thermally denatured fibrinogen and crosslinked fibrin coated surfaces, BigmgiSJTols, 19,2129-2138. 

Spraggon, G., et al. Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin. Nature 389 455-462, 1997. 

Fibrin is an elastic filamentous protein elaborated from its precursor, fibrinogen, which is present in plasma at high concentration. Fibrin is formed in response to the actions of thrombin. Thrombin cleaves small peptides from the fibrinogen molecule, forming fibrin monomers that will begin to polymerize and become crosslinked. 

Fibrinolytics. Figure 2 Various fibrin structures for plasmin. Fibrinogen (Fg) is converted to fibrin (F) by thrombin (T), and thrombin can also convert factor XIII (XIII) to activated factor XIII (Xllla). The latter produces crosslinks between fibrins (FxxF) and also may crosslink fibrin with a2-plasmin inhibitor (FxxFxxPI). The efficiency of digestion of these plasmin substrates by plasmin, resulting in the soluble fibrin degradation products (FDP), is different. The amount of FDP formed in time is expressed in arbitrary units. 

Both intrinsic and extrinsic pathways generate activated factor X. This protease, in turn, catalyses the proteolytic conversion of prothrombin (factor II) into thrombin (Ha). Thrombin, in turn, catalyses the proteolytic conversion of fibrinogen (I) into fibrin (la). Individual fibrin molecules aggregate to form a soft clot. Factor XHIa catalyses the formation of covalent crosslinks between individual fibrin molecules, forming a hard clot (Figures 12.3 and 12.4). 

Fibrin polymerization is initiated by the enzymatic cleavage of the fibrinopeptides, converting fibrinogen to fibrin monomer (Fig. 1). Then, several nonenzymatic reactions yield an orderly sequence of macromolec-ular assembly steps. Several other plasma proteins bind specifically to the resulting fibrin network. The clot is stabilized by covalent ligation or crosslinking of specific amino acids by a transglutaminase, Factor XHIa. 

K.R. Siebenlist, D.A. Meh, M.W. Mosesson, Protransglutaminase (factor Xlll) mediated crosslinking of fibrinogen and fibrin, Thromb. Haemost. 86 (2001) 1221-1228. 

G. Spraggon, S.J. Everse, and R.S. Doolittle, Crystal Structures of Fragment D from Human Fibrinogen and its Crosslinked Counterpart from Fibrin. Nature, 389,455-462,1997. 

Figure 4 Schematic representation of the polymerization of fibrin and fibrinolysis. Fibrinogen molecules are soluble in the blood until thrombin cleaves the A fibrinopeptides, yielding desA fibrin monomer, which assemble in a half-staggered fashion to make two-stranded protofibrils. Factor Xllla rapidly crosslinks the adjacent y chains. The B fibrinopeptides are cleaved more slowly mosdy after polymerization begins. On cleavage of the B fibrinopeptides, the aC domains are released, bringing protofibrils together more efficiendy to produce thicker fibers. Factor Xllla crosslinks the a chains more slowly, to stabilize the clot more fully. Plasminogen is converted to plasmin by tissue plasminogen activator on the fibrin surface plasmin cleaves specific peptide bonds (arrows) to dissolve the clot.

Fibrinogen, fibrinogen fragment D, crosslinked fibrin, noncrosslinked fibrin D-Glucan-protein complex (Saccharomyces cerevisiae) Glutathione... 

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