Tissue-Type Plasminogen Activator Is a Multiligand Cross-β Structure Receptor

Abstract

Tissue-type plasminogen activator (tPA) regulates fibrin clot lysis by stimulating the conversion of plasminogen into the active protease plasmin. Fibrin is required for efficient tPA-mediated plasmin generation and thereby stimulates its own proteolysis. Several fibrin regions can bind to tPA, but the structural basis for this interaction is unknown. Amyloid beta (Abeta) is a peptide aggregate that is associated with neurotoxicity in brains afflicted with Alzheimer's disease. Like fibrin, it stimulates tPA-mediated plasmin formation. Intermolecular stacking of peptide backbones in beta sheet conformation underlies cross-beta structure in amyloid peptides. We show here that fibrin-derived peptides adopt cross-beta structure and form amyloid fibers. This correlates with tPA binding and stimulation of tPA-mediated plasminogen activation. Prototype amyloid peptides, including Abeta and islet amyloid polypeptide (IAPP) (associated with pancreatic beta cell toxicity in type II diabetes), have no sequence similarity to the fibrin peptides but also bind to tPA and can substitute for fibrin in plasminogen activation by tPA. Moreover, the induction of cross-beta structure in an otherwise globular protein (endostatin) endows it with tPA-activating potential. Our results classify tPA as a multiligand receptor and show that cross-beta structure is the common denominator in tPA binding ligands.

Design of a Partial Peptide Mimetic of Anginex with Antiangiogenic and Anticancer Activity

“…This Ile-Val-Leu presentation pattern is also present in 6DBF7 (␤-strand 2) along with the cross-strand hydrophobic pattern Val-Met-Leu (␤-strand 1). Although the efficacy of the Flt-1 peptide is much less than that of 6DBF7, this structural/ compositional similarity between these two peptides suggests that, on the molecular level, the ␤-sheet structure of these molecules is pivotal to their activity (37), which may suggest signaling through a common cellular receptor.…”

Endogenous Inhibitors of Angiogenesis

“…Such different endostatin conformations have distinct effects on plasminogen activation. Insoluble endostatin stimulates plasminogen activation, whereas soluble endostatin has no effect on plasminogen activation (58).…”

Amyloid-based nanosensors and nanodevices

“…Fibrin is primarily involved in blood clotting and platelet activation mechanisms, regulated by tissue-type plasminogen activator, which is a regulator of fibrin clot lysis. 119,120 Interestingly, several amyloidogenic peptides, namely amyloid beta-peptide and fibrin-derived amyloidogenic sequences interact with tissue-type plasminogen activator, 120 suggesting additional roles for amyloidogenic sequences in the modulation of the activity of other biomolecules. Furthermore, amyloid conformers of endostatin were reported to possess anti-angiogenic activity.…”