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Jekyll and Hyde protein in brain disease?


28 October 2005

A new peptide that may be able to reverse the formation of amyloid fibrils in the brain could be the key to a cure for Alzheimer's. 

Amyloid fibrils form insoluble plaques which are one of the hallmarks of Alzheimer's disease. The amyloid-forming proteins, which transform to make the fibrils, can exist harmlessly in the brain, provided they have the right secondary structure. 

Amyloid fibrils form from chains of beta-sheet protein fragments. Researchers at the Free University of Berlin, Germany, think that if the structural change from alpha-helix to beta-sheet can be stopped then the destruction of brain tissue and the onset of disease could be prevented. 

Beate Koksch and colleagues designed a 26 amino acid peptide with a Jekyll and Hyde character. The peptide can convert between an alpha-helical structure and a fibril forming beta-sheet structure without breaking any peptide bonds, in a similar way to the amyloid-forming protein. 

 

                           scheme

 

While using this peptide to study what effect environment had on secondary structure, the team found a way to reverse the fibril formation. A very stable alpha-helix with complementary amino acids to the fibril peptide is the key to this reversal. This can turn the beta-sheet fibril structures back into alpha-helices by binding to them to form super helices that contain two alpha-helices wrapped around each other. 

The future of brain disease prevention may therefore involve introducing a complementary stable alpha-helix in this way before fibril formation can occur.  

Wendy E M Crocker 

 

References

K Pagel, T Vagt and B Koksch, Org. Biomol. Chem., 2005, 3, 3843 (DOI:10.1039/b510098d)