On the nucleation of amyloid β‐protein monomer folding

Neurotoxic assemblies of the amyloid β‐protein (Aβ) have been linked strongly to the pathogenesis of Alzheimer's disease (AD). Here, we sought to monitor the earliest step in Aβ assembly, the creation of a folding nucleus, from which oligomeric and fibrillar assemblies emanate. To do so, limite...

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Bibliographic Details
Published in:Protein science 2005-06, Vol.14 (6), p.1581-1596
Main Authors: Lazo, Noel D., Grant, Marianne A., Condron, Margaret C., Rigby, Alan C., Teplow, David B.
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Alzheimer's disease
amyloid
Amyloid beta-Peptides - chemistry
Amyloid beta-Peptides - metabolism
amyloid β‐protein
Animals
Asp‐N, endoproteinase AspN
Aβ, amyloidβ‐protein
CT, chymotrypsin
DQF‐COSY, double‐quantum filtered correlation spectroscopy
folding nucleus
GluC, endoproteinase Glu‐C
HNE, human neutrophil elastase
Humans
NOESY, nuclear Overhauser enhancement spectroscopy
PPE, porcine pancreatic elastase
Protein Folding
Protein Structure, Secondary
ROESY, rotating‐frame Overhauser enhancement spectroscopy
RP‐HPLC, reverse‐phase high‐performance liquid chromatography
TH, thermolysin
TOCSY, total correlation spectroscopy
TR, trypsin
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Summary:Neurotoxic assemblies of the amyloid β‐protein (Aβ) have been linked strongly to the pathogenesis of Alzheimer's disease (AD). Here, we sought to monitor the earliest step in Aβ assembly, the creation of a folding nucleus, from which oligomeric and fibrillar assemblies emanate. To do so, limited proteolysis/mass spectrometry was used to identify protease‐resistant segments within monomeric Aβ(1–40) and Aβ(1–42). The results revealed a 10‐residue, protease‐resistant segment, Ala21–Ala30, in both peptides. Remarkably, the homologous decapeptide, Aβ(21–30), displayed identical protease resistance, making it amenable to detailed structural study using solution‐state NMR. Structure calculations revealed a turn formed by residues Val24–Lys28. Three factors contribute to the stability of the turn, the intrinsic propensities of the Val‐Gly‐Ser‐Asn and Gly‐Ser‐Asn‐Lys sequences to form a β‐turn, long‐range Coulombic interactions between Lys28 and either Glu22 or Asp23, and hydrophobic interaction between the isopropyl and butyl side chains of Val24 and Lys28, respectively. We postulate that turn formation within the Val24–Lys28 region of Aβ nucleates the intramolecular folding of Aβ monomer, and from this step, subsequent assembly proceeds. This model provides a mechanistic basis for the pathologic effects of amino acid substitutions at Glu22 and Asp23 that are linked to familial forms of AD or cerebral amyloid angiopathy. Our studies also revealed that common C‐terminal peptide segments within Aβ(1–40) and Aβ(1–42) have distinct structures, an observation of relevance for understanding the strong disease association of increased Aβ(1–42) production. Our results suggest that therapeutic approaches targeting the Val24–Lys28 turn or the Aβ(1–42)‐specific C‐terminal fold may hold promise.
ISSN:0961-8368
1469-896X
DOI:10.1110/ps.041292205