Physical basis of amyloid fibril polymorphism

Abstract

Polymorphism is a key feature of amyloid fibril structures but it remains challenging to explain these variations for a particular sample. Here, we report electron cryomicroscopy-based reconstructions from different fibril morphologies formed by a peptide fragment from an amyloidogenic immunoglobulin light chain. The observed fibril morphologies vary in the number and cross-sectional arrangement of a structurally conserved building block. A comparison with the theoretically possible constellations reveals the experimentally observed spectrum of fibril morphologies to be governed by opposing sets of forces that primarily arise from the β-sheet twist, as well as peptide–peptide interactions within the fibril cross-section. Our results provide a framework for rationalizing and predicting the structure and polymorphism of cross-β fibrils, and suggest that a small number of physical parameters control the observed fibril architectures.

A Substantial Structural Conversion of the Native Monomer Leads to in‐Register Parallel Amyloid Fibril Formation in Light‐Chain Amyloidosis

“…Two recent studies determined secondary‐structure elements of the V L s from AL‐09 and MAK33 light‐chain fibrils, both belonging to the κ‐family . In‐register parallel arrangements of β‐sheets have been suggested for short light‐chain fragments in the context of cryo‐EM studies . One currently lacking central element is the quaternary structure of the mature fibrils formed by the full‐length protein …”

Production of BBF2H7‐derived small peptide fragments via endoplasmic reticulum stress‐dependent regulated intramembrane proteolysis

“…44 However, the predicted structure of BBF2H7 does not contain β-sheet structures. High aggregation propensity of BSP fragments is supported by the following results: 1) BSP fragments showed high hydrophobicity by Kyte-Doolittle analysis, 2) synthetic BSP fragments exhibited SDS-resistant oligomerization, and 3) synthetic BSP fragments facilitated the formation of fibrils during incubation at 37°C.…”

An Efficient, Robust New Scheme for Establishing Broadband Homonuclear Correlations in Biomolecular Solid State NMR

“…Continuous technological and conceptual developments have endowed contemporary high‐resolution solid‐state nuclear magnetic resonance (NMR) spectroscopy, with capabilities that rival those of solution‐state NMR when tackling structural and dynamic investigations of large biomolecules . When performing such studies the problem of spectral assignment and resolution nearly invariably arises, demanding the use of high‐dimensional NMR experiments correlating labeled 13 C‐ and/or 15 N sites in the biomolecule.…”