Tissue-type plasminogen activator is a multiligand cross-β structure receptor

Tissue-type plasminogen activator (tPA) regulates fibrin clot lysis by stimulating the conversion of plasminogen into the active protease plasmin [1]. Fibrin is required for efficient tPA-mediated plasmin generation and thereby stimulates its own proteolysis. Several fibrin regions can bind to tPA [1], 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 [2]. Like fibrin, it stimulates tPA-mediated plasmin formation [3-6]. Intermolecular stacking of peptide backbones in beta sheet conformation underlies cross-beta structure in amyloid peptides [6]. 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 11 diabetes [7]), 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-P structure is the common denominator in tPA binding ligands.