Savignygrin, a Platelet Aggregation Inhibitor from the Soft TickOrnithodoros savignyi, Presents the RGD Integrin Recognition Motif on the Kunitz-BPTI Fold

• Published in: The Journal of biological chemistry Vol. 277; no. 24; pp. 21371 - 21378
• Main Authors: Mans, Ben J., Louw, Abraham I., Neitz, Albert W.H.
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 01.06.2002
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112060200

Savignygrin, a platelet aggregation inhibitor that possesses the RGD integrin recognition motif, has been purified from the soft tick Ornithodoros savignyi . Two isoforms with similar biological activities differ because of R52G and N60G in their amino acid sequences, indicating a recent gene duplication event. Platelet aggregation induced by ADP (IC 50 , 130 n m ), collagen, the thrombin receptor-activating peptide, and epinephrine was inhibited, although platelets were activated and underwent a shape change. The binding of α-CD41 (P2) to platelets, the binding of purified α IIb β 3 to fibrinogen, and the adhesion of platelets to fibrinogen was inhibited, indicating a targeting of the fibrinogen receptor. In contrast, the adhesion of osteosarcoma cells that express the integrin α v β 3 to vitronectin or fibrinogen was not inhibited, indicating the specificity of savignygrin toward α IIb β 3 . Savignygrin shows sequence identity to disagregin, a platelet aggregation inhibitor from the tick Ornithodoros moubata that lacks an RGD motif. The cysteine arrangement of savignygrin is similar to that of the bovine pancreatic trypsin inhibitor family of serine protease inhibitors. A homology model based on the structure of the tick anticoagulant peptide indicates that the RGD motif is presented on the substrate-binding loop of the canonical BPTI inhibitors. However, savignygrin did not inhibit the serine proteases fXa, plasmin, thrombin, or trypsin. This is the first report of a platelet aggregation inhibitor that presents the RGD motif using the Kunitz-BPTI protein fold.