How Single Site Mutations Can Help Understanding Structure Formation of Amyloid β₁₋₄₀

Abstract

Amyloid fibrils represent the structural endpoint on the energetic (mis)folding landscape of very many proteins. Physiologically, amyloid fibrils are observed as a characteristic hallmark in misfolding diseases often associated with degenerative and neurodegenerative disorders. In the beginning of the scientific discussion, the focus is laid on the fibrillar state, but over the time it becomes increasingly clear that low molecular weight and transient aggregates are of crucial importance for pathological mechanisms. Structural studies find different intra‐ and intermolecular contacts for the most well‐studied peptide amyloid β (Aβ) depending on the stage of fibrillation. In particular, the contact between residues phenylalanine 19 (F19) and leucine 34 (L34) seems to be highly conserved, suggesting that it must be of particular significance for Aβ misfolding and possibly the pathological properties of the peptide. This review aims to highlight the rational and the usefulness of point mutations in Aβ peptides and their impact on the critical interstrand contact F19−L34 depending on the stage of fibrillation. While the amyloid structure of Aβ is very robust against quite a few modifications, the toxicity of mutated Aβ molecules highly depends on the F19−L34 contact.

Thermoplasmonic Manipulation for the Study of Single Polymers and Protein Aggregates

“…[88] Many of the characteristics of the structure of these fibrillar aggregates are known, for example, from sophisticated cryoEM [89] and NMR experiments. [90] As the 𝛽-sheet conformation of the peptides in the fibrils differs from the free functional monomers, the growth of the elongated fibrillar structures is expected to follow a nucleation and growth process. [91][92][93] Equation (9) reveals an example of the master equation for the time evolution of the concentration of aggregates f of size j,…”

Conformation of Pyroglutamated Amyloid β (3–40) and (11–40) Fibrils – Extended or Hairpin?

“…While the Gly 25 –Ile 31 contact seems to be a unique interaction in this new extended model, it is important to note that this model also involves contacts so far assumed to be indicative of a hairpin conformation. For instance, the residues Phe 19 and Leu 34 , which are extensively described as potentially both intra- or intermolecular contacts ,− in different hairpin models (Figure A). The same holds true for Ala 21 and Leu 34 , which were identified as intramolecular contact in a slightly different hairpin model by the Bertini laboratory .…”