TY - JOUR
T1 - Assemblies of Alzheimer's peptides Aβ25-35 and Aβ31-35
T2 - Reverse-turn conformation and side-chain interactions revealed by X-ray diffraction
AU - Bond, Jeremy P.
AU - Deverin, Sean P.
AU - Inouye, Hideyo
AU - El-Agnaf, Omar M.A.
AU - Teeter, Martha M.
AU - Kirschner, Daniel A.
N1 - Funding Information:
The authors thank Dr. Ann Yee for valuable assistance with the electron microscopy. The research was supported by an Alzheimer’s Association/T.L.L. Temple Discovery Award (D.A.K.), the Alzheimer’s Disease Research Program of the American Health Assistance Foundation (D.A.K.), and institutional support from Boston College.
PY - 2003/2/1
Y1 - 2003/2/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Amyloid
KW - Antagonist
KW - G-protein-coupled receptor
KW - Neurotoxicity
KW - Reverse turn
KW - Substance P
KW - Tachykinin
KW - X-ray diffraction
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U2 - 10.1016/S1047-8477(02)00625-1
DO - 10.1016/S1047-8477(02)00625-1
M3 - Article
C2 - 12615542
AN - SCOPUS:0037291289
SN - 1047-8477
VL - 141
SP - 156
EP - 170
JO - Journal of Structural Biology
JF - Journal of Structural Biology
IS - 2
ER -