Plasmin Cleavage of the Amyloid β-Protein: Alteration of Secondary Structure and Stimulation of Tissue Plasminogen Activator Activity
| Autor: | M Porter, W E Van Nostrand |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Amyloid beta
Plasmin Proteolysis Peptide Arginine Biochemistry Tissue plasminogen activator Protein Structure Secondary Enzyme activator medicine Humans Histidine Fibrinolysin chemistry.chemical_classification Amyloid beta-Peptides biology medicine.diagnostic_test Circular Dichroism Hydrolysis Molecular biology Peptide Fragments In vitro Enzyme Activation Kinetics chemistry Tissue Plasminogen Activator biology.protein Protein Processing Post-Translational Plasminogen activator medicine.drug |
| Zdroj: | Biochemistry. 38:11570-11576 |
| ISSN: | 1520-4995 0006-2960 |
| Popis: | Cerebrovascular amyloid beta-protein (A beta) deposition, a key pathological feature of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis Dutch-type, can lead to intracerebral hemorrhage; however, the mechanism for this remains unclear. Assembled A beta is a potent stimulator of tissue-type plasminogen activator (tPA) in vitro. Herein, we investigated the stimulation of tPA by freshly solubilized A beta 1-40. The rate of tPA stimulation by A beta 1-40 increased dramatically over time, suggesting that A beta may be altered during the course of the reaction. SDS-PAGE analysis showed that A beta 1-40 was cleaved during the course of the reaction. Subsequent studies showed that it was plasmin, the product of tPA activation of plasminogen, that specifically cleaved A beta 1-40 in the amino terminal region between Arg5 and His6. Plasmin effectively cleaved a chromogenic substrate corresponding to this cleavage site in A beta. Circular dichroism spectral analysis showed that A beta 6-40 adopted a strong beta-sheet secondary structure. This truncated A beta 6-40 peptide was a potent stimulator of tPA in vitro. Our results indicate that beta-sheet secondary structure of A beta, which can be promoted by plasmin cleavage, stimulates tPA activity. These findings suggest that pathologic interactions between A beta, tPA, and plasmin in the cerebral vessel wall could result in excessive proteolysis contributing to intracerebral hemorrhages. |
| Databáze: | OpenAIRE |
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