Assemblies of Alzheimer's peptides Aβ25-35 and Aβ31-35: Reverse-turn conformation and side-chain interactions revealed by X-ray diffraction

Jeremy P. Bond, Sean P. Deverin, Hideyo Inouye, Omar Ali El-Agnaf, Martha M. Teeter, Daniel A. Kirschner

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Alzheimer's β amyloid protein (Aβ) is a 39 to 43 amino acid peptide that is a major component in the neuritic plaques of Alzheimer's disease (AD). The assemblies constituted from residues 25-35 (Aβ25-35), which is a sequence homologous to the tachykinin or neurokinin class of neuropeptides, are neurotoxic. We used X-ray diffraction and electron microscopy to investigate the structure of the assemblies formed by Aβ25-35 peptides and of various length sequences therein, and of tachykinin-like analogues. Most solubilized peptides after subsequent drying produced diffraction patterns characteristic of β-sheet structure. Moreover, the peptides Aβ31-35 (Ile-Ile-Gly-Leu-Met) and tachykinin analogue Aβ(Phe31)31-35 (Phe-Ile-Gly-Leu-Met) gave powder diffraction patterns to 2.8Å Bragg spacing. The observed reflections were indexed by an orthogonal unit cell having dimensions of a=9.36Å, b=15.83Å, and c=20.10Å for the native Aβ31-35 peptide, and a=9.46Å, b=16.22Å, and c=11.06Å for the peptide having the Ile31Phe substitution. The initial model was a β strand where the hydrogen bonding, chain, and intersheet directions were placed along the a, b, and c axes. An atomic model was fit to the electron density distribution, and subsequent refinement resulted in R factors of 0.27 and 0.26, respectively. Both peptides showed a reverse turn at Gly33 which results in intramolecular hydrogen bonding between the antiparallel chains. Based on previous reports that antagonists for the tachykinin substance P require a reverse turn, and that Aβ is cytotoxic when it is oligomeric or fibrillar, we propose that the tachykinin-like Aβ31-35 domain is a turn exposed at the Aβ oligomer surface where it could interact with the ligand-binding site of the tachykinin G-protein-coupled receptor.

Original languageEnglish
Pages (from-to)156-170
Number of pages15
JournalJournal of Structural Biology
Volume141
Issue number2
DOIs
Publication statusPublished - 1 Feb 2003
Externally publishedYes

Fingerprint

Tachykinins
X-Ray Diffraction
Peptides
Hydrogen Bonding
Powder Diffraction
Serum Amyloid A Protein
R Factors
Amyloid Plaques
Substance P
Sequence Homology
G-Protein-Coupled Receptors
Neuropeptides
Electron Microscopy
Alzheimer Disease
Binding Sites
Electrons
Ligands
Amino Acids

Keywords

  • Alzheimer's disease
  • Amyloid
  • Antagonist
  • G-protein-coupled receptor
  • Neurotoxicity
  • Reverse turn
  • Substance P
  • Tachykinin
  • X-ray diffraction

ASJC Scopus subject areas

  • Structural Biology

Cite this

Assemblies of Alzheimer's peptides Aβ25-35 and Aβ31-35 : Reverse-turn conformation and side-chain interactions revealed by X-ray diffraction. / Bond, Jeremy P.; Deverin, Sean P.; Inouye, Hideyo; Ali El-Agnaf, Omar; Teeter, Martha M.; Kirschner, Daniel A.

In: Journal of Structural Biology, Vol. 141, No. 2, 01.02.2003, p. 156-170.

Research output: Contribution to journalArticle

Bond, Jeremy P. ; Deverin, Sean P. ; Inouye, Hideyo ; Ali El-Agnaf, Omar ; Teeter, Martha M. ; Kirschner, Daniel A. / Assemblies of Alzheimer's peptides Aβ25-35 and Aβ31-35 : Reverse-turn conformation and side-chain interactions revealed by X-ray diffraction. In: Journal of Structural Biology. 2003 ; Vol. 141, No. 2. pp. 156-170.
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abstract = "Alzheimer's β amyloid protein (Aβ) is a 39 to 43 amino acid peptide that is a major component in the neuritic plaques of Alzheimer's disease (AD). The assemblies constituted from residues 25-35 (Aβ25-35), which is a sequence homologous to the tachykinin or neurokinin class of neuropeptides, are neurotoxic. We used X-ray diffraction and electron microscopy to investigate the structure of the assemblies formed by Aβ25-35 peptides and of various length sequences therein, and of tachykinin-like analogues. Most solubilized peptides after subsequent drying produced diffraction patterns characteristic of β-sheet structure. Moreover, the peptides Aβ31-35 (Ile-Ile-Gly-Leu-Met) and tachykinin analogue Aβ(Phe31)31-35 (Phe-Ile-Gly-Leu-Met) gave powder diffraction patterns to 2.8{\AA} Bragg spacing. The observed reflections were indexed by an orthogonal unit cell having dimensions of a=9.36{\AA}, b=15.83{\AA}, and c=20.10{\AA} for the native Aβ31-35 peptide, and a=9.46{\AA}, b=16.22{\AA}, and c=11.06{\AA} for the peptide having the Ile31Phe substitution. The initial model was a β strand where the hydrogen bonding, chain, and intersheet directions were placed along the a, b, and c axes. An atomic model was fit to the electron density distribution, and subsequent refinement resulted in R factors of 0.27 and 0.26, respectively. Both peptides showed a reverse turn at Gly33 which results in intramolecular hydrogen bonding between the antiparallel chains. Based on previous reports that antagonists for the tachykinin substance P require a reverse turn, and that Aβ is cytotoxic when it is oligomeric or fibrillar, we propose that the tachykinin-like Aβ31-35 domain is a turn exposed at the Aβ oligomer surface where it could interact with the ligand-binding site of the tachykinin G-protein-coupled receptor.",
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