Limited Plasmin Proteolysis of Vitronectin

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Abstract
The adhesion protein vitronectin is associated with extracellular matrices and serves as cofactor for plasminogen-activator inhibitor-1. Limited proteolysis by plasmin converts vitronectin into defined fragments which are detectable at sites of inflammation and angiogenesis. The loss and gain of binding functions of vitronectin fragments for macromolecular ligands was characterized in the present study. The initially generated 61–63-kDa vitronectin-(1–348)-fragment serves as typical binding component for plasminogen and binding function was lost upon carboxypeptidase B treatment indicating the importance of a C-terminal lysine. Complementary binding sites reside in isolated plasminogen kringles 1–3 (designated angiostatin) as deduced from direct binding and ligand blotting experiments. A synthetic vitronectin-(331–348)-peptide from the C-terminus of the 61–63-kDa fragment could mimic plasminogen and angiostatin binding. Also, the immobilized peptide bound tissue plasminogen-activator and mediated plasmin formation, comparable to fibrinogen-derived peptides. The 61–63-kDa vitronectin fragment was indistinguishable in its adhesive properties to intact vitronectin and bound active but not latent plasminogen-activator inhibitor-1. Late plasminolysis of vitronectin resulted in the processing of the N-terminal region of the protein with the generation of 42 kDd3S-kDa fragments that had Gly89 as new N-terminus and that were ineffective in promoting cell adhesion. Thus, at sites of cell-matrix interactions which become proteolytically modified by plasmin during inflammatory and angiogenic processes, vitronectin serves as plasminogen/angiostatin-binding factor. Due to this differential change in functions particularly at sites of deposition in the vascular system or at wound sites vitronectin is considered to be an important morpho-regulatory factor.