Switching off neurodegenerative disease

Proof that peptide secondary structures can be switched by metal ions has been provided by a model based on a well known protein motif. 

Secondary-structure transformations that are dependent on metal ions seem to be common in the early stages of neurodegenerative diseases including Alzheimer's, Parkinson's and prion diseases such as Creutzfeld-Jakob disease, where the concentration of metal ions in brain tissue is naturally high. 

helix-pleated sheet

Peptide and protein folding can be controlled

Beate Koksch and co-workers from the Free University of Berlin, Germany, used an alpha-helical coiled coil as a template for their peptide model. Coiled coils are ubiquitous protein motifs and involve two identical amino acid strands wrapped around each other - similar to the strands in a rope. Koksch's group added histidine residues to the peptide, creating potential sites for Cu2+ and Zn2+ ions to form complexes. 

When metal ions were added the alpha-helical content was found to decrease as beta-sheet content increased. Adding EDTA (ethyl-enediaminetetraacetic acid) to capture the metal ions reversed this effect, proving that the switch between secondary structures can be regulated. 

Inhibiting the formation of protein aggregates is critical in developing efficient therapies for neurodegenerative diseases. 'The capability to design peptides and proteins, which can be controlled in terms of their folding and their aggregation behaviour, is probably one of the most fundamental requests on modern peptide chemistry,' said Koksch. 

Kathryn Sear




K Pagel et alOrg. Biomol. Chem., 2005, 3, 2500 (DOI: 10.1039/b505979h)