title: Differential effects of Phe19 and Phe20 on fibril formation by amyloidogenic peptide A beta 16-22 (Ac-KLVFFAE-NH2).
abstract: The sequence KLVFFAE (A beta 16-22) in Alzheimer's beta-amyloid is thought to be a core beta-structure that could act as a template for folding other parts of the polypeptide or molecules into fibrillar assemblies rich in beta-sheet. To elucidate the mechanism of the initial folding process, we undertook combined X-ray fiber/powder diffraction and infrared (IR) spectroscopy to analyze lyophilized A beta 16-22 and solubilized/dried peptide containing nitrile probes at F19 and/or F20. Solubilized/dried wild-type (WT) A beta 16-22 and the peptide containing cyanophenylalanine at F19 (19CN) or at F20 (20CN) gave fiber patterns consistent with slab-like beta-crystallites that were cylindrically averaged around the axis parallel to the polypeptide chain direction. The WT and 19CN assemblies showed 30-A period arrays arising from the stacking of the slabs along the peptide chain direction, whereas the 20CN assemblies lacked any such stacking. The electron density projection along the peptide chain direction indicated similar side-chain dispositions for WT and 20CN, but not for 19CN. These X-ray results and modeling imply that in the assembly of WT A beta 16-22 the F19 side chain is localized within the intersheet space and is involved in hydrophobic contact with amino acids across the intersheet space, whereas the F20 side chain localized near the slab surface is less important for the intersheet interaction, but involved in slab stacking. IR observations for the same peptides in dilute solution showed a greater degree of hydrogen bonding for the nitrile groups in 20CN than in 19CN, supporting this interpretation.
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Inouye
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Gleason
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.forename: Sean M
authors.initials: SM
authors.lastname: Decatur
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kirschner
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry; D019943:Amino Acid Substitution; D000682:Amyloid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D005612:Freeze Drying; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D009570:Nitriles / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D010649:Phenylalanine / Q000737:chemistry* / Q000031:analogs & derivatives; D033362:Powder Diffraction; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013499:Surface Properties
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D009570:Nitriles; D009842:Oligopeptides; D010446:Peptide Fragments; C417223:amyloid beta-protein (16-22); C530634:p-cyanophenylalanine; D010649:Phenylalanine; D000409:Alanine