title: Probing the amyloid-beta(1-40) fibril environment with substituted tryptophan residues.
abstract: A signature feature of Alzheimer's disease is the accumulation of plaques, composed of fibrillar amyloid-beta protein (Abeta), in the brain parenchyma. Structural models of Abeta fibrils reveal an extensive beta-sheet network with a hydrophobic core extending throughout the fibril axis. In this study, phenylalanines in the Abeta(1-40) sequence were substituted with tryptophan residues at either position 4 (F4W) or 19 (F19W) to probe the fibril environment. The F4W substitution did not alter self-assembly kinetics, while the F19W change slightly lengthened the lag phase without hindering fibril formation. The tryptophan fluorescence of Abeta(1-40) F19W, but not Abeta(1-40) F4W, underwent a marked blue shift during fibril formation and this shift was temporally correlated with thioflavin T binding. Isolated Abeta(1-40) F19W fibrils exhibited the largest fluorescence blue shifts consistent with W19 insertion into the Abeta(1-40) fibril inner core and direct probing of the substantially hydrophobic environment therein.
authors.affiliation: Department of Chemistry and Biochemistry and Center for Nanoscience, University of Missouri-St. Louis, St. Louis, MO 63121, USA.
authors.forename: Jillienne C
authors.initials: JC
authors.lastname: Touchette
authors.forename: Laura L
authors.initials: LL
authors.lastname: Williams
authors.forename: Deepa
authors.initials: D
authors.lastname: Ajit
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallazzi
authors.forename: Michael R
authors.initials: MR
authors.lastname: Nichols
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D052160:Benzothiazoles; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000378:metabolism; D014364:Tryptophan
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T; D014364:Tryptophan