11 May 2023

For decades, the structures of repetitive, flexible folds of amyloid fibrils eluded X-ray crystallographers, but with the advent of cryo-electron microscopy, these elusive amyloids were no longer able to hide. An explosion of published structures followed within a few years (reviewed in Sawaya et al., 2021). How to keep track of this growing cast of characters, and draw scientific knowledge from them? Enter the Amyloid Atlas.

Spearheaded by Michael Sawaya at the University of California, Los Angeles, the database depicts the important molecular characteristics of amyloid folds. This includes pathogenic ones—such as the contortions taken by Aβ, tau, and α-synuclein—as well as functional configurations, such as amyloids that generate membraneless organelles. In all, the atlas includes 261 structures at present, some being different polymorphs of the same protein. For example, 68 entries are dedicated to tau’s many twists. Soon, there will be 69, as researchers recently resolved the structure of tau filaments residing within extracellular vesicles, which were slightly different from those described in brain homogenates (May 2023 news). 

Why build this resource? Amyloid structures account for 0.1 percent of the more than 200,000 structures catalogued within the Protein Data Bank, a public database of all published structures. This makes amyloid folds difficult to track down and compare. What’s more, PDB entries lack detailed information about the molecular features of the structures, such as how specific residues are arranged in space. Researchers need this information to understand and target these often-nefarious proteins.

With support from the National Institutes on Aging, Sawaya started building the online atlas two years ago. At first, progress was excruciatingly slow. Sawaya used PDB coordinates to manually reconstruct the structures and map their molecular features. To keep up with the flood of new data, Sawaya developed a program to automatically render data-rich illustrations from published structures. UCLA’s David Eisenberg played a central role in developing algorithms used to calculate the stability of protein structures in the database, while Jose Rodriguez, also at UCLA, helped modify these algorithms to suit amyloid structures specifically. Sawaya updates the Amyloid Atlas every month.

What can one expect to find in there? Structures are organized alphabetically by protein; some proteins have several entries if they adopt different amyloid folds. For each, the source of the amyloid, the method used to resolve the structure, its resolution, and link to original paper are listed, along with two illustrations: a polarity map and an energy map.

Two Flavors of Tau. Two structural polymorphs of 3R/4R tau fibrils reported in 2017 are listed as separate entries in the Amyloid Atlas. [Courtesy of Michael Sawaya, UCLA.]

The polarity map features labeled residues that are color-coded by charge. As opposed to schematics that depict all residues as equally sized circles, these maps show the space occupied by each residue, Sawaya noted. Using this truer atomic representation, researchers can estimate where ligands, co-factors, or potential inhibitors might bind (see image below).

Polarity Brings Clarity. A tau protofilament, depicted in an oversimplified schematic (left) versus a polarity map (right). The latter shows charge, polarity, and space occupied by each residue, enabling inferences about ligand binding and other characteristics. [Courtesy of Michael Sawaya, UCLA.]

Each entry also includes an energy map of the amyloid structure. This is a map of the stability of the structure. Residues that stabilize the structure, such as those involved in stacks of aromatic side chains, are designated in red; destabilizing residues are blue. Sawaya noted that pathogenic amyloid proteins tend to be highly stable, while functional amyloids tend to be more labile, folding and unfolding depending on the environmental conditions. Researchers can use these energy maps to find regions of a given amyloid fold that may be essential for its structure, or kinks in its armor that may be amenable for therapeutic targeting.

Loose or Stable? In an energy map, each residue is color-coded based on how much it contributes to the stability of the structure. Red residues are highly stable, blue ones are not. Aβ42 (right) is far more stable than FUS (left).

Sawaya isn’t the only one who can create these maps. Along with the Atlas, he created Amyloid Illustrator, where researchers can enter the coordinates of their newly resolved structures to create their own maps, and compare them to others already catalogued in the database. Sawaya hopes scientists will start incorporating the maps within their published papers, as well. So far, at least one, reporting the cryo-EM structure of a pathogenic amyloid fold in the β₂-microgloblin protein, has depicted a map created within the atlas (Wilkinson et al., 2023).—Jessica Shugart

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References

News Citations

1. Tau Filaments Found Tethered Inside Alzheimer's Brain Exosomes 11 May 2023

Paper Citations

1. Sawaya MR, Hughes MP, Rodriguez JA, Riek R, Eisenberg DS. The expanding amyloid family: Structure, stability, function, and pathogenesis. Cell. 2021 Sep 16;184(19):4857-4873. PubMed.
2. Wilkinson M, Gallardo RU, Martinez RM, Guthertz N, So M, Aubrey LD, Radford SE, Ranson NA. Disease-relevant β2-microglobulin variants share a common amyloid fold. Nat Commun. 2023 Mar 2;14(1):1190. PubMed.

External Citations

1. Amyloid Atlas

Further Reading

External Links

1. Amyloid Atlas