Fibrinogen hydrophobic association

Formation of a blood clot involves a complex cascade of enzymatically controlled reactions the penultimate step of which is the formation of thrombin. Thrombin then cleaves peptides from fibrinogen to form fibrin monomers that associate to form the fibrin clot. Fibrin clot formation is a carefully poised process whereby a relatively minor injury will not allow excessive bleeding and result in death and whereby excessive clot formation will not block blood flow and result in death. As will be seen by examination of the relevant molecular structures, regardless of the balance struck, the key process of clot formation is the hydrophobic association of fibrin monomers. In demonstrating this perspective, the same T,-based mean residue hydrophobicity plot will be used as was used above in Figure 7.9 for understanding the hydrophobic association of hemoglobin subunits. 

The mean residue hydrophobicity plot of BP-fibrinogen in Figure 7.30B exhibits two minor hydrophobic sequences near residues 115 and 375 that could serve hydrophobic folding and assembly within the fibrinogen molecule, but would be less likely to participate in the hydrophobic association between molecules. 

S Thrombin Activation of Fibrinogen Provides for Hydrophobic Association to Form the Soft Fibrin Clot... 

Accordingly, by simple inspection of the mean hydrophobicity plot for y-fibrinogen, we see the activation of fibrinogen as the emergence of a site for hydrophobic association with the most hydrophobic sequence in a second molecule. 

X-ray analysis of crystals of iohexol and serine proteinase (pancreaticporcine elastase) reveals that three molecules of iohexol are associated with elastase, with one close to the active site (subsite SI), the second in the vicinity of in subsites S2/S3, and the third located in a pocket at the surface of the protein. The association is a result of the affinity of iohexol directed toward the hydrophobic regions of the enzyme and supports the hypothesis of the contrast medium s potent inhibition of thrombin. Another example of the contrast medium-protein interaction is between iopamidol and fibrinogen or lysozyme... 

Figure 7.28. Stereo view of fibrinogen, ((xPy)2, showing three sites for intermolecular contacts resulting in formation of the fibrin clot (1) the end-to-end docking site for linear fiber growth that works in cooperation with association at the Ea site (2) the Ea site of the carboxyl-terminal y-globule hydrophobic domain, which provides for fibrin formation in a second dimension due to association with the GPRP of an a-amino terminus (at the central domain) that was exposed on removal of the 16 residue A peptide ...

Figure 7.29. Single residue (A) and mean residue (B) hydrophobicity plots of human y-fibrinogen. The most striking feature of the mean residue plot is the hydrophobic sequence, residues 337 to 379, experimentally shown to provide the Ea site for interaction with the a-chain amino-terminus on removal of the A peptide and exposure of GPRP and its surrounding hydrophobic residues for association with the hydrophobic domain of the Ea site shown in Figure...

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