Atomic Resolution Structure of Monomorphic Aβ₄₂ Amyloid Fibrils

Abstract

Amyloid-β (Aβ) is a 39–42 residue protein produced by the cleavage of the amyloid precursor protein (APP), which subsequently aggregates to form cross-β amyloid fibrils that are a hallmark of Alzheimer’s disease (AD). The most prominent forms of Aβ are Aβ1–40 and Aβ1–42, which differ by two amino acids (I and A) at the C-terminus. However, Aβ42 is more neurotoxic and essential to the etiology of AD. Here, we present an atomic resolution structure of a monomorphic form of AβM01–42 amyloid fibrils derived from over 500 13C−13C, 13C−15N distance and backbone angle structural constraints obtained from high field magic angle spinning NMR spectra. The structure (PDB ID: 5KK3) shows that the fibril core consists of a dimer of Aβ42 molecules, each containing four β-strands in a S-shaped amyloid fold, and arranged in a manner that generates two hydrophobic cores that are capped at the end of the chain by a salt bridge. The outer surface of the monomers presents hydrophilic side chains to the solvent. The interface between the monomers of the dimer shows clear contacts between M35 of one molecule and L17 and Q15 of the second. Intermolecular 13C−15N constraints demonstrate that the amyloid fibrils are parallel in register. The RMSD of the backbone structure (Q15–A42) is 0.71 ± 0.12 Å and of all heavy atoms is 1.07 ± 0.08 Å. The structure provides a point of departure for the design of drugs that bind to the fibril surface and therefore interfere with secondary nucleation and for other therapeutic approaches to mitigate Aβ42 aggregation.

Modulation of amyloid assembly by glycosaminoglycans: from mechanism to biological significance

“…The third model was proposed from fibrils grown in the presence of amyloids extracted from brain tissue of a patient afflicted with Alzheimer's disease and is also composed by a three-fold rotational symmetry (Lu et al 2013). Two models were recently proposed for Aβ(1-42) fibrils in which monomers adopt an S-shape and are composed of four short β-strands (Colvin et al 2016;Wälti et al 2016). Thus, these studies highlight that the addition of two additional amino acids at the C-terminal end can lead to drastic alterations of the amyloid structure, indicating that fibril morphology is very sensitive to modifications within the primary sequence.…”

Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity

“…2c). This is fundamentally different from the structure of the pathological and irreversible fibril of Aβ42 (Colvin et al 2016), which is mostly stabilized by hydrophobic interactions (I of Fig. 2d).…”

Mammalian amyloidogenic proteins promote prion nucleation in yeast

“…Several variants of Aβ peptide exist in humans, of which Aβ1-42 and Aβ1-40 (lacking the last two amino acid residues) are the most abundant ones [41]. Of these two, Aβ1-42 is considered to be the most amyloidogenic and most pathogenic form in humans [30,42] Nucleation of a yeast prion by mammalian proteins structural models placing the N-terminal region of Aβ outside of amyloid core [43,44].…”

“…This peptide is drastically inefficient in prion nucleation in the yeast assay, compared to the highly amyloidogenic and presumably pathogenic Aβ42 (Fig 5A). While previous structural studies used the in vitro produced Aβ40 polymers [48,49] the high resolution structures of Aβ42 amyloids, mostly based on solid state NMR have also been reported recently [43,44,50]. These structures include two molecules per polymer unit, and five β intermolecular sheets spanning residues 2-6 (β1), 15-18 (β2), 26-28 (β3), 30-32 (β4), and 39-42 (β5) per each "half" of the fibril.…”