title: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
authors.forename: Christopher J A
authors.initials: CJ
authors.lastname: Warner
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
authors.forename: Subrata
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
authors.forename: Alejandro R
authors.initials: AR
authors.lastname: Foley
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
authors.forename: Eefei
authors.initials: E
authors.lastname: Chen
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Kliger
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
authors.forename: Jevgenij A
authors.initials: JA
authors.lastname: Raskatov
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D006801:Humans; D009154:Mutation; D017433:Protein Structure, Secondary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides
keywords: Alzheimer's disease; amyloid β; chirality; circular dichroism; familial mutations