Using chiral peptide substitutions to probe the structure function relationship of a key residue of Aβ42

Abstract

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 β-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 β-sheet characteristics. Our approach can be extended to other residues of Aβ, as well as further amyloidogenic peptides.

Aggregation and Amyloidogenicity of the Nuclear Coactivator Binding Domain of CREB‐Binding Protein

“…A complementary approach that may help to explore conformational space and to identify conformational states that have distinct aggregation properties and the predisposition to self‐assemble into amyloids, is to modify the chirality of polypeptide . It was shown that the site‐specific incorporation of d ‐amino acids into Alzheimer's disease‐related Aβ‐peptide can drastically alter its aggregation properties, allowing locations in the sequence that are critical for amyloidogenicity to be identified . Moreover, in many examples, adding mirror‐image analogues ( d ‐enantiomers) of amyloidogenic peptides or proteins to its native l ‐counterpart was reported to facilitate formation of amyloid fibers .…”

The rippled β-sheet layer configuration—a novel supramolecular architecture based on predictions by Pauling and Corey

“…The rippled b-sheet layer configuration-a novel supramolecular architecture based on predictions by Pauling and Corey † Introduction Tailored proteins and peptides hold immense potential for materials development and biomedical application. Chiral (i.e., D-amino acid) substitutions may be employed to generate selfassembling peptide architectures with unique properties, [1][2][3][4][5][6] bioactive compounds with distinct activities, [7][8][9][10][11][12][13] as well as systems with enhanced crystallization behavior. [14][15][16][17][18] There is great interest in developing new peptidic systems that contain Damino acid substitutions, as this would allow systematic access to a vast structural space with unique molecular properties.…”

Biophysical characterization as a tool to predict amyloidogenic and toxic properties of amyloid‐β42 peptides

“…The structural and functional differences observed with the synthetics 2 and 3 may reflect the intrinsic drawbacks of chemically synthesized peptides (e.g., trace impurities and racemization). For example, incorporating D-amino acids into synthetic mimetics has been reported to affect the b-sheet formation and aggregation kinetics of Ab peptide in comparison with physiologically relevant L-amino acid peptides [52,53]. Moreover, D-and L-stereoisomers cannot be separated by conventional RP-HPLC and repeated purification steps with commercially available, synthetic Ab42 preparations (typically 95% purity) cannot eliminate problematic HPLC impurities [28].…”