Amyloid fibrils formed from different proteins, each associated with a particular disease, contain a common cross-β spine. The atomic architecture of a spine, from the fibril-forming segment GNNQQNY of the yeast prion protein Sup35, was recently revealed by X-ray microcrystallography. It is a pair of β-sheets, with the facing side chains of the two sheets interdigitated in a dry ‘steric zipper’. Here we report some 30 other segments from fibril-forming proteins that form amyloid-like fibrils, microcrystals, or usually both. These include segments from the Alzheimer’s amyloid-β and tau proteins, the PrP prion protein, insulin, islet amyloid polypeptide (IAPP), lysozyme, myoglobin, α-synuclein and β2-microglobulin, suggesting that common structural features are shared by amyloid diseases at the molecular level. Structures of 13 of these microcrystals all reveal steric zippers, but with variations that expand the range of atomic architectures for amyloid-like fibrils and offer an atomic-level hypothesis for the basis of prion strains. Degenerative diseases such as Alzheimer's and Parkinson's are associated with the precipitation of amyloid fibrils in the brain. The fibrils are remarkably uniform in structure, considering the diversity of the proteins that produce them. Sawaya et al. have now identified 30 short fibril-forming peptides taken from a large range of amyloid diseases and have solved the atomic structures of crystals formed by 13 of them. All the peptides so far examined self-assemble by forming variants of the 'steric zipper', a structural feature first found in the yeast prion protein Sup 35. The zipper may be a key to the strength of amyloid fibrils, and is a prime target for therapeutic intervention. Degenerative diseases such as Alzheimer's or Parkinson's are associated with the misfolding of many diverse proteins, yet the amyloid fibrils formed by all these proteins are similar. David Eisenberg and colleagues have now identified 30 short fibril-forming peptides implicated in a range of amyloid diseases and have solved 13 of their atomic structures, revealing variations in one common feature — the 'steric zipper'.

/pdf/atomic-structures-of-amyloid-cross-beta-spines-reveal-varied-dl3fy0h04s.pdf

Atomic structures of amyloid cross-beta spines reveal varied steric zippers.

One hundred years ago a small group of psychiatrists described the abnormal protein deposits in the brain that define the most common neurodegenerative diseases Over the past 25 years, it has become clear that the proteins forming the deposits are central to the disease process Amyloid-β and tau make up the plaques and tangles of Alzheimer's disease, where these normally soluble proteins assemble into amyloid-like filaments Tau inclusions are also found in a number of related disorders Genetic studies have shown that dysfunction of amyloid-β or tau is sufficient to cause dementia The ongoing molecular dissection of the neurodegenerative pathways is expected to lead to a true understanding of disease pathogenesis

https://science.sciencemag.org/content/sci/314/5800/777.full.pdf

A Century of Alzheimer's Disease

The phenomenon of protein aggregation and amyloid formation has become the subject of rapidly increasing research activities across a wide range of scientific disciplines. Such activities have been stimulated by the association of amyloid deposition with a range of debilitating medical disorders, from Alzheimer's disease to type II diabetes, many of which are major threats to human health and welfare in the modern world. It has become clear, however, that the ability to form the amyloid state is more general than previously imagined, and that its study can provide unique insights into the nature of the functional forms of peptides and proteins, as well as understanding the means by which protein homeostasis can be maintained and protein metastasis avoided.

The amyloid state and its association with protein misfolding diseases

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors a...

Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade

The amyloid state of proteins in human diseases

Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (Abeta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Abeta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a beta-strand-turn-beta-strand motif that contains two intermolecular, parallel, in-register beta-sheets that are formed by residues 18-26 (beta1) and 31-42 (beta2). At least two molecules of Abeta(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand beta1 of the nth molecule and the even-numbered residues of strand beta2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Abeta fibril growth. It also provides a structural basis for fibrillization inhibitors.

https://www.pnas.org/content/pnas/102/48/17342.full.pdf

3D structure of Alzheimer's amyloid-β(1–42) fibrils

The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of alpha-synuclein (alpha-syn) from monomers by intermediates into amyloid fibrils is the toxic disease-causative mechanism. Here, we studied the structure of alpha-syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five beta-strands within the fibril core comprising residues 35-96 and solid-state NMR data from amyloid fibrils comprising the fibril core residues 30-110 confirmed the presence of beta-sheet secondary structure. The data suggest that beta1-strand interacts with beta2, beta2 with beta3, beta3 with beta4, and beta4 with beta5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of approximately 2 x 3.5 nm. Based on the combination of these data and published structural studies, a fold of alpha-syn in the fibrils is proposed and discussed.

https://www.pnas.org/content/pnas/105/25/8637.full.pdf

Dominique Riek-Loher

Papers

3D structure of Alzheimer's amyloid-β(1–42) fibrils

The fold of alpha-synuclein fibrils