Tissue-type plasminogen activator is a multiligand cross-beta structure receptor.

Area of Science:

• Biochemistry and Molecular Biology
• Proteolysis and Fibrinolysis
• Neurodegenerative Diseases and Protein Aggregation

Background:

• Tissue-type plasminogen activator (tPA) is crucial for dissolving blood clots by activating plasminogen to plasmin.
• Fibrin significantly enhances tPA activity, but the molecular basis for fibrin-tPA interaction remains unclear.
• Amyloid-beta (Abeta) peptides, implicated in Alzheimer's disease, also stimulate tPA activity.

Purpose of the Study:

• To elucidate the structural basis for fibrin's interaction with tissue-type plasminogen activator (tPA).
• To investigate whether amyloid structures can mediate tPA binding and activation.
• To classify the binding properties of tPA and identify common features of its ligands.

Main Methods:

• Analysis of fibrin-derived peptides for cross-beta structure formation.
• Assessment of tPA binding to fibrin peptides and various amyloid peptides (Abeta, IAPP).
• Measurement of tPA-mediated plasminogen activation in the presence of fibrin, amyloid peptides, and modified proteins.

Main Results:

• Fibrin-derived peptides were shown to adopt amyloidogenic cross-beta structures, correlating with tPA binding and activation.
• Prototype amyloid peptides (Abeta, IAPP) bound to tPA and substituted for fibrin in promoting plasminogen activation.
• Inducing cross-beta structure in endostatin conferred tPA-activating potential, irrespective of sequence homology.

Conclusions:

• Cross-beta structure is the common molecular feature enabling ligand binding to tissue-type plasminogen activator (tPA).
• tPA functions as a multiligand receptor, recognizing the cross-beta structural motif present in both fibrin and amyloid aggregates.
• This finding links fibrinolysis regulation to the structural properties of amyloid peptides, with implications for diseases like Alzheimer's.