FIGURE 5.

Model for the mechanism of angiostatin formation from plasmin(ogen). The Cys⁴⁶²-Cys⁵⁴¹ disulfide bond is reduced in a fraction of plasminogen in blood or in the injured vascular wall. We propose that binding of PGK to plasmin induces a conformational change in kringle 5 that leads to attack by the Cys⁵⁴¹ thiolate anion (present as a certain percentage of all thiols by action of the buffer) on the Cys⁵³⁶ sulfur atom of the Cys⁵¹²-Cys⁵³⁶ disulfide bond, resulting in reduction of the bond. Cleavage of the disulfide allows further conformational change and exposure of the peptide backbone to proteolysis C-terminal of residues 468, 474, and 530 (represented by wavy red lines).