title: Mutations that replace aromatic side chains promote aggregation of the Alzheimer's Aβ peptide.
abstract: The aggregation of polypeptides into amyloid fibrils is associated with a number of human diseases. Because these fibrils--or intermediates on the aggregation pathway--play important roles in the etiology of disease, considerable effort has been expended to understand which features of the amino acid sequence promote aggregation. One feature suspected to direct aggregation is the π-stacking of aromatic residues. Such π-stacking interactions have also been proposed as the targets for various aromatic compounds that are known to inhibit aggregation. In the case of Alzheimer's disease, the aromatic side chains Phe19 and Phe20 in the wild-type amyloid beta (Aβ) peptide have been implicated. To explicitly test whether the aromaticity of these side chains plays a role in aggregation, we replaced these two phenylalanine side chains with leucines or isoleucines. These residues have similar sizes and hydrophobicities as Phe but are not capable of π-stacking. Thioflavin-T fluorescence and electron microscopy demonstrate that replacement of residues 19 and 20 by Leu or Ile did not prevent aggregation, but rather enhanced amyloid formation. Further experiments showed that aromatic inhibitors of aggregation are as effective against Ile- and Leu-substituted versions of Aβ42 as they are against wild-type Aβ. These results suggest that aromatic π-stacking interactions are not critical for Aβ aggregation or for the inhibition of Aβ aggregation.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States.
authors.forename: Anne H
authors.initials: AH
authors.lastname: Armstrong
authors.forename: Jermont
authors.initials: J
authors.lastname: Chen
authors.forename: Angela Fortner
authors.initials: AF
authors.lastname: McKoy
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hecht
mesh_terms: D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D024322:Amino Acids, Aromatic / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007532:Isoleucine / Q000235:genetics; D007930:Leucine / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics
chemical_list: D024322:Amino Acids, Aromatic; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D007532:Isoleucine; D010649:Phenylalanine; D007930:Leucine; D000409:Alanine