The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation

Cukalevski, Risto; Yang, Xiaoting; Meisl, Georg; Weininger, Ulrich; Bernfur, Katja; Frohm, Birgitta; Knowles, Tuomas P. J.; Linse, Sara

doi:10.1039/c4sc02517b

Cited by 125 publications

(205 citation statements)

References 62 publications

(132 reference statements)

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“…That is, the Aβ(1-42) fibril exhibits increased peptide-peptide interactions across the dimer interface compared with the Aβ(1-40) fibril, which is in agreement with the higher aggregation propensity of Aβ (1-42) (3). iv) The difference in dimer packing interfaces in Aβ and Aβ(1-42) fibrils agrees with the limited ability of the two peptide variants to form mixed fibrils in vitro (4). v) Our model predicts that the charged residues Glu22 and Asp23 prevent more favorable packing at the dimer interface ( Fig.…”

Section: Discussionsupporting

confidence: 54%

Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM

Schmidt

Rohou

Lasker

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

201

197

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Alzheimer's disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) peptide oligomers and fibrils. These structures may damage the brain and give rise to cerebral amyloid angiopathy, neuronal dysfunction, and cellular toxicity. Although the connection between AD and Aβ fibrillation is extensively documented, much is still unknown about the formation of these Aβ aggregates and their structures at the molecular level. Here, we combined electron cryomicroscopy, 3D reconstruction, and integrative structural modeling methods to determine the molecular architecture of a fibril formed by Aβ(1-42), a particularly pathogenic variant of Aβ peptide. Our model reveals that the individual layers of the Aβ fibril are formed by peptide dimers with face-to-face packing. The two peptides forming the dimer possess identical tilde-shaped conformations and interact with each other by packing of their hydrophobic C-terminal β-strands. The peptide C termini are located close to the main fibril axis, where they produce a hydrophobic core and are surrounded by the structurally more flexible and charged segments of the peptide N termini. The observed molecular architecture is compatible with the general chemical properties of Aβ peptide and provides a structural basis for various biological observations that illuminate the molecular underpinnings of AD. Moreover, the structure provides direct evidence for a steric zipper within a fibril formed by full-length Aβ peptide.protein aggregation | protein folding | cross-β | Frealix

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Section: Discussionsupporting

confidence: 54%

Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM

Schmidt

Rohou

Lasker

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

201

197

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“…65 Twelve hydrophobic side chains (L17, F19, F20, V24, A30, I31, I32, L34, M35, V36, V39, and I41) are largely exposed to solvent in the unstructured monomer and buried in the fibril. This suggests that the self-assembly reaction is governed by the hydrophobic effect and increased entropy of water upon desolvation.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, in mixtures, A β 40 and A β 42 fail to form mixed fibrils; they interact only at the level of primary nucleation, while the fibril-specific processes are highly specific events. 80 The two residues I41–A42 cannot be accommodated in A β 40 structures for steric reasons, as there is no room to fit two more residues next to V40. However, removal of the same residues from the A β 42 fibril structure presented here would lead to very significant destabilization because one of the hydrophobic cores would be disrupted by removal of V41.…”

Section: Resultsmentioning

confidence: 99%

Atomic Resolution Structure of Monomorphic Aβ₄₂ Amyloid Fibrils

et al. 2016

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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.

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“…Indeed, kinetic measurements of aggregation of Aβ 42 in general show a shorter kinetic lag time/half time than that do measurements on Aβ 40 at the same inital monomer concentration. 38,39 The two species also differ in their secondary nucleation behavior according to experiments. 40 We remark that some of the mis-stacked prefibrillar oligomer clusters resemble the structures we might imagine to occur in secondary nucleation.…”

Section: Discussionmentioning

confidence: 99%

Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1–42) and Amyloid Beta(1–40)

2017

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Using a predictive coarse-grained protein force field, we compute and compare the free energy landscapes and relative stabilities of amyloid-β protein (1-42) and amyloid-β protein (1-40) in their monomeric and oligomeric forms up to the octamer. At the same concentration, the aggregation free energy profile of Aβ42 is more downhill, with a computed solubility that is about ten times smaller than that of Aβ40. At a concentration of 40 μM, the clear free energy barrier between the prefibrillar tetramer form and the fibrillar pentamer in the Aβ40 aggregation landscape disappears for Aβ42, suggesting that the Aβ42 tetramer has a more diverse structural range. To further compare the landcapes, we develop a cluster analysis based on the structural similarity between configurations and use it to construct an oligomerization map that captures the paths of easy interconversion between different but structurally similar states of oligomers for both species. A taxonomy of the oligomer species based on β-sheet stacking topologies is proposed. The comparison of the two oligomerization maps highlights several key differences in the landscapes that can be attributed to the two additional C-terminal residues that Aβ40 lacks. In general, the two terminal residues strongly stabilize the oligomeric structures for Aβ42 relative to Aβ40, and greatly facilitate the conversion from prefibrillar trimers to fibrillar tetramers.

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The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation

Abstract: Reaction network starting from monomer mixtures of Aβ40 and Aβ42. Interaction at the level of primary nucleation only accelerates Aβ40 fibril formation. Separate fibrils form as secondary nucleation and elongation are highly specific.

Cited by 125 publications

References 62 publications

Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM

Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM

Atomic Resolution Structure of Monomorphic Aβ₄₂ Amyloid Fibrils

Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1–42) and Amyloid Beta(1–40)

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The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation

Abstract: Reaction network starting from monomer mixtures of Aβ40 and Aβ42. Interaction at the level of primary nucleation only accelerates Aβ40 fibril formation. Separate fibrils form as secondary nucleation and elongation are highly specific.

Cited by 125 publications

References 62 publications

Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM

Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM

Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils

Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1–42) and Amyloid Beta(1–40)

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Atomic Resolution Structure of Monomorphic Aβ₄₂ Amyloid Fibrils