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Coagulation factor XI is activated in vitro by factor XIIa in the presence of high molecular weight kininogen (HMWK) and a negatively charged surface. Factor XII deficiency is not associated with bleeding, which suggests that another mechanism for factor XI activation exists in vivo. A revised model of coagulation is proposed in which factor XI is activated by thrombin. In the absence of cofactors, thrombin is more effective (kcat/Km = 1.6 x 10(5)) than factor XIIa (1.7 x 10(4)) in activating factor XI. Dextran sulfate enhances activation of factor XI by thrombin 2000-fold; part of this effect is due to autoactivation of factor XI by activated factor XI.
We describe chemical synthesis of peptide mixtures that equally express many sequence combinations. Using 65 couplings of single amino acids, five mixtures were prepared with the sequences Tyr-Gly-Arg-Gly-Yyy-Xxx-Xxx, where Yyy is Ser, Asp, Arg, Asn, or Glu, and Xxx is any amino acids. Compositional and sequence analyses supported full representation of all amino acids, except isoleucine was deficient in the sixth position. The data suggest formation of a repertoire of 1,900 sequence combinations (5 x 19 x 20). The mixture with Asp as the fifth residue inhibited platelet adhesion to fibronectin more effectively than the other mixtures. Peptide libraries offer a new tool for investigating bioactive peptides.
We have used platelets as a model system to study the function of c-src in signal transduction and cell adhesion. Numerous proteins were found to be phosphorylated on tyrosine in response to thrombin-induced platelet activation and aggregation. Two phases of phosphorylation were observed, with the second phase, but not the first, being inhibited by blocking platelet aggregation with an Arg-Gly-Asp-Ser tetrapeptide. As a first step towards identifying those proteins phosphorylated on tyrosine and to determine the specific role of p60src during platelet activation, we looked for changes in p60src kinase activity and for associations of p60src with other tyrosine phosphoproteins. The data presented here demonstrate an increase in p60src kinase activity within 1 min of thrombin-induced activation. Furthermore, p60src transiently associates with a tyrosine phosphoprotein during platelet activation and aggregation. This tyrosine phosphoprotein, p80/85, is a previously characterized cytoskeletal substrate for v-src in transformed cells. The data presented here suggest a model in which p60src functions in platelets to link upstream events, such as cell-surface adhesive interactions, with changes in platelet shape and cytoskeletal organization.