Structural requirements of fibrinogen Aα-(148 - 160) for the enhancement of the rate of plasminogen activation by tPA

Fibrin, not fibrinogen, enhances the rate of tPA catalysed plasminogen activation. In earlier studies we have shown that a site involved in this rate enhancement is located in a tridecapeptide, i.e. fibrinogen Aα-(148 −160). This sequence comprises a special charge distribution in which a stretch with alternating neutral and acidic amino acids is embraced by basic amino acids. In this study we found that the disruption of charge distribution as caused by replacing valine 152 by other (charged and/or polar) amino acids leads to loss of rate-enhancing capacity. Also lysine at position Aa-157 was replaced by lysine derivatives and other amino acids. We found that the side chain of the amino acid at position Aa-157 must contain no (as in glycine) or one carbon atom without substitution (alanine). When the side chain contains two or more carbon atoms, there should also be a polar group in the side chainWe also synthesized a series of hexapeptides covering the sequence of Aα-(148− 160), and found that only Aα-(154− 159) is stimulatory, notwithstanding the fact that the peptides Aα(152 - 157), Aα(153 - 158) and Aα-(155 - 160) also contain lysine Aα-157