The Alzheimer β‐peptide shows temperature‐dependent transitions between left‐handed 3₁‐helix, β‐strand and random coil secondary structures

Abstract

The temperature‐induced structural transitions of the full length Alzheimer amyloid β‐peptide [Aβ(1–40) peptide] and fragments of it were studied using CD and 1H NMR spectroscopy. The full length peptide undergoes an overall transition from a state with a prominent population of left‐handed 31 (polyproline II; PII)‐helix at 0 °C to a random coil state at 60 °C, with an average ΔH of 6.8 ± 1.4 kJ·mol−1 per residue, obtained by fitting a Zimm–Bragg model to the CD data. The transition is noncooperative for the shortest N‐terminal fragment Aβ(1–9) and weakly cooperative for Aβ(1–40) and the longer fragments. By analysing the temperature‐dependent 3JHNHα couplings and hydrodynamic radii obtained by NMR for Aβ(1–9) and Aβ(12–28), we found that the structure transition includes more than two states. The N‐terminal hydrophilic Aβ(1–9) populates PII‐like conformations at 0 °C, then when the temperature increases, conformations with dihedral angles moving towards β‐strand at 20 °C, and approaches random coil at 60 °C. The residues in the central hydrophobic (18–28) segment show varying behaviour, but there is a significant contribution of β‐strand‐like conformations at all temperatures below 20 °C. The C‐terminal (29–40) segment was not studied by NMR, but from CD difference spectra we concluded that it is mainly in a random coil conformation at all studied temperatures. These results on structural preferences and transitions of the segments in the monomeric form of Aβ may be related to the processes leading to the aggregation and formation of fibrils in the Alzheimer plaques.

Discriminating early stage Aβ42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study

“…(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Recent evidence supports the view that, at the monomeric level, the ensemble of Aβ is a mixture of multiple, nearly isoenergenic conformational species, in agreement with the energy landscape view of protein dynamics proposed by Frauenfelder and coworkers (22).…”

SOD1 aggregation in ALS mice shows simplistic test tube behavior

“…2B). Conformationwise, the precursor of SOD1 fibrillation seems, thus, equivalent to those of intrinsically disordered proteins, like α-synuclein (21), polyQ (30), and the Aβ-peptide (29,31). Changing by mutation the SOD1 stability in ALS mice yields similar results, manifested in an R 2 = 0.92 correlation between survival times and tissue concentration of unfolded SOD1 (Fig.…”

Intermediacy of Poly(l-proline) II and β-Strand Conformations in Poly(l-lysine) β-Sheet Formation Probed by Temperature-Jump/UV Resonance Raman Spectroscopy

“…Since then, PPII structure has been identified in numerous unfolded peptides by various spectroscopic methods. These proteins include the unstructured Aβ peptide fragment (Aβ , pH 4)(7), the full length peptide and a several N-terminal fragments (Aβ , Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)16,28) pH 7.4, 0°C) (12), the reduced ovine PrP 93-244 (pH 4.0), unfolded poly (K) (13), ribonuclease A(14) and a 7 residue non-helical alanine peptide (XAO) (15). Studies of short alanine peptides reveal that the unfolded conformation is primarily PPII structure (15)(16)(17)(18).…”