Differential effects of Phe19 and Phe20 on fibril formation by amyloidogenic peptide AB16-22 (Ac-KLVFFAE-NH2)

Title:
Differential effects of Phe19 and Phe20 on fibril formation by amyloidogenic peptide AB16-22 (Ac-KLVFFAE-NH2)
Authors:
Inouye, Hideyo; Gleason, Katherine A.; Decatur, Sean M.; Kirschner, Daniel A.
Abstract:
The sequence KLVFFAE (Aβ16–22) in Alzheimer's β-amyloid is thought to be a core β-structure that could act as a template for folding other parts of the polypeptide or molecules into fibrillar assemblies rich in β-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 Aβ16–22 and solubilized/dried peptide containing nitrile probes at F19 and/or F20. Solubilized/dried wild-type (WT) Aβ16–22 and the peptide containing cyanophenylalanine at F19 (19CN) or at F20 (20CN) gave fiber patterns consistent with slab-like β-crystallites that were cylindrically averaged around the axis parallel to the polypeptide chain direction. The WT and 19CN assemblies showed 30-Å 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 Aβ16–22 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.
Citation:
Inouye, H., K.A. Gleason, S.M. Decatur, and D.A. Kirschner. 2010. "Differential effects of Phe19 and Phe20 on fibril formation by amyloidogenic peptide AB16-22 (Ac-KLVFFAE-NH2)." Proteins: Structure, Function, And Bioinformatics 78: 2306-2321.
Publisher:
Wiley Blackwell for Wiley-Liss
DATE ISSUED:
2010
Department:
Chemistry
Type:
article
PUBLISHED VERSION:
10.1002/prot.22743
PERMANENT LINK:
http://hdl.handle.net/11282/309416

Full metadata record

DC FieldValue Language
dc.contributor.authorInouye, Hideyoen_US
dc.contributor.authorGleason, Katherine A.en_US
dc.contributor.authorDecatur, Sean M.en_US
dc.contributor.authorKirschner, Daniel A.en_US
dc.date.accessioned2013-12-23T16:09:13Z-
dc.date.available2013-12-23T16:09:13Z-
dc.date.issued2010en
dc.identifier.citationInouye, H., K.A. Gleason, S.M. Decatur, and D.A. Kirschner. 2010. "Differential effects of Phe19 and Phe20 on fibril formation by amyloidogenic peptide AB16-22 (Ac-KLVFFAE-NH2)." Proteins: Structure, Function, And Bioinformatics 78: 2306-2321.en_US
dc.identifier.issn0887-3585en_US
dc.identifier.urihttp://hdl.handle.net/11282/309416-
dc.description.abstractThe sequence KLVFFAE (Aβ16–22) in Alzheimer's β-amyloid is thought to be a core β-structure that could act as a template for folding other parts of the polypeptide or molecules into fibrillar assemblies rich in β-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 Aβ16–22 and solubilized/dried peptide containing nitrile probes at F19 and/or F20. Solubilized/dried wild-type (WT) Aβ16–22 and the peptide containing cyanophenylalanine at F19 (19CN) or at F20 (20CN) gave fiber patterns consistent with slab-like β-crystallites that were cylindrically averaged around the axis parallel to the polypeptide chain direction. The WT and 19CN assemblies showed 30-Å 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 Aβ16–22 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.en_US
dc.publisherWiley Blackwell for Wiley-Lissen_US
dc.identifier.doi10.1002/prot.22743-
dc.subject.departmentChemistryen_US
dc.titleDifferential effects of Phe19 and Phe20 on fibril formation by amyloidogenic peptide AB16-22 (Ac-KLVFFAE-NH2)en_US
dc.typearticleen_US
dc.identifier.journalProteins: Structure, Function, And Bioinformaticsen_US
dc.identifier.volume78en_US
dc.identifier.startpage2306en_US
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