Using chiral peptide substitutions to probe the structure function relationship of a key residue of A beta 42

作者：Warner Christopher J A; Dutta Subrata; Foley Alejandro R; Chen Eefei; Kliger David S; Raskatov Jevgenij A^*

来源：Chirality, 2017, 29(1): 5-9.

DOI：10.1002/chir.22667

• Alzheimer's disease
• amyloid beta
• chirality
• circular dichroism
• familial mutations

Amyloid beta-protein 42 plays an important role in the onset and progression of Alzheimer's disease. Familial mutations have identified the glutamate residue 22 as a hotspot with regard to peptide neurotoxicity. We introduce an approach to study the influence of systematic sidechain modification at this residue, employing chirality as a structural probe. Circular dichroism experiments reveal that charge-preserving alterations of the amino acid sidechain attenuate the characteristic random coil to beta-sheet transition associated with the wildtype peptide. Removal of the negative charge from residue 22, a trait observed with all known familial mutations at this residue, gives rise to a peptide with limited random coil propensity and high beta-sheet characteristics. Our approach can be extended to other residues of A beta, as well as further amyloidogenic peptides.

• 出版日期2017-1